Glucopyranosyl-substituted phenyl derivates, medicaments containing such compounds, their use and process for their manufacture

ABSTRACT

Glucopyranosyl-substituted benzene derivatives of general formula I 
     
       
         
         
             
             
         
       
     
     where the groups R 1  to R 6  as well as R 7a , R 7b , R 7c  are defined herein and the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

RELATED APPLICATIONS

This application claims benefit of under 35 U.S.C. 119(e) filed No.60/560,239 Apr. 7, 2004, from German application number DE1 02004012676.3 filed Mar. 16, 2004, from German application numberDE102004040168.3 filed Aug. 18, 2004, and from German application numberDE102004061145.9 filed Dec. 16, 2004, the contents of which areincorporated herein.

DESCRIPTION OF THE INVENTION

The present invention relates to glucopyranosyl-substituted benzenederivatives of general formula I

wherein the groups R¹ to R⁶ and R^(7a), R^(7b), R^(7c) are as definedhereinafter, including the tautomers, the stereoisomers, the mixturesthereof and the salts thereof. The invention further relates topharmaceutical compositions containing a compound of formula I accordingto the invention as well as the use of a compound according to theinvention for preparing a pharmaceutical composition for the treatmentof metabolic disorders. In addition, the invention relates to processesfor preparing a pharmaceutical composition as well as a compoundaccording to the invention.

In the literature, compounds which have an inhibitory effect on thesodium-dependent glucose cotransporter SGLT2 are proposed for thetreatment of diseases, particularly diabetes.

Glucopyranosyloxy-substituted aromatic groups and the preparationthereof and their possible activity as SGLT2 inhibitors are known frompublished International applications WO 98/31697, WO 01/27128, WO02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/013118,WO 2004/052902, WO 2004/052903 and US application US 2003/0114390.

AIM OF THE INVENTION

The aim of the present invention is to find new pyranosyloxy-substitutedbenzene derivatives, particularly those which are active with regard tothe sodium-dependent glucose cotransporter SGLT, particularly SGLT2. Afurther aim of the present invention is to discoverpyranosyloxy-substituted benzene derivatives which have an enhancedinhibitory effect on the sodium-dependent glucose cotransporter SGLT2 invitro and/or in vivo compared with known, structurally similar compoundsand/or have better pharmacological or pharmacokinetic properties.

A further aim of the present invention is to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofmetabolic disorders, particularly diabetes.

The invention also sets out to provide a process for preparing thecompounds according to the invention.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

OBJECT OF THE INVENTION

In a first aspect the present invention relates toglucopyranosyloxy-substituted benzene derivatives of general formula I

wherein

-   R¹ is selected from the definitions of the group A and    -   if R³ is selected from the definitions of the group B, R¹ may        additionally also be selected from the meanings hydrogen,        fluorine, chlorine, bromine, iodine, C₁₋₄-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkyl, C₂₋₄-alkynyl-C₁₋₄-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkoxy, C₂₋₄-alkynyl-C₁₋₄-alkoxy,        C₃₋₇-cycloalkyl-C₁₋₄-alkyl, C₅₋₇-cycloalkenyl-C₁₋₄-alkyl, a        methyl group substituted by 1 to 3 fluorine atoms, an ethyl        group substituted by 1 to 5 fluorine atoms, C₁₋₄-alkoxy, a        methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy        group substituted by 1 to 5 fluorine atoms, a C₁₋₄-alkyl group        substituted by a hydroxy or C₁₋₃-alkoxy group, a C₂₋₄-alkoxy        group substituted by a hydroxy or C₁₋₃-alkoxy group,        C₃₋₆-cycloalkyl-C₁₋₃-alkoxy or hydroxy,    -   while in the above-mentioned cycloalkyl and cycloalkenyl rings        one or two methylene groups may be replaced independently of one        another by O or CO, and-   R² denotes hydrogen, fluorine, chlorine, bromine, hydroxy,    C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano or nitro, while the alkyl or alkoxy    group may be mono- or polysubstituted by fluorine, and-   R³ is selected from the definitions of the group B and    -   if R¹ is selected from the definitions of the group A, R³ may        additionally also be selected from the meanings hydrogen,        fluorine, chlorine, bromine, iodine, C₁₋₆-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkyl, C₂₋₄-alkynyl-C₁₋₄-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkoxy, C₂₋₄-alkynyl-C₁₋₄-alkoxy,        C₃₋₇-cycloalkyl, C₅₋₇-cycloalkenyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl,        C₅₋₇-cycloalkenyl-C₁₋₄-alkyl, C₃₋₆-cycloalkylidenmethyl,        hydroxy, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₃-alkoxy, aryl,        aryl-C₁₋₃-alkyl, heteroaryl, heteroaryl-C₁₋₃-alkyl, aryloxy,        aryl-C₁₋₃-alkyl-oxy, a methyl or methoxy group substituted by 1        to 3 fluorine atoms, a C₂₋₄-alkyl or C₂₋₄-alkoxy group        substituted by 1 to 5 fluorine atoms, a C₁₋₄-alkyl group        substituted by a cyano group, a C₁₋₄-alkyl group substituted by        a hydroxy or C₁₋₃-alkyloxy group, cyano, carboxy,        C₁₋₃-alkoxycarbonyl, aminocarbonyl, (C₁₋₃-alkylamino)carbonyl,        di-(C₁₋₃-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl,        piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl,        (C₁₋₄-alkyl)carbonylamino, C₁₋₄-alkylsulphonylamino,        C₁₋₄-alkylsulphanyl, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,        arylsulphonylamino, aryl-C₁₋₃-alkylsulphonylamino or        arylsulphonyl,-   R⁴, R⁵ independently of one another denote hydrogen, fluorine,    chlorine, bromine, iodine, cyano, nitro, C₁₋₃-alkyl, C₁₋₃-alkoxy,    methyl or methoxy substituted by 1 to 3 fluorine atoms,-   A denotes C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl, C₃₋₇-cycloalkyl,    C₅₋₇-cycloalkenyl, aryl, heteroaryl, C₁₋₄-alkylcarbonyl,    arylcarbonyl, heteroarylcarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,    pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,    4-(C₁₋₄-alkyl)piperazin-1-ylcarbonyl, arylaminocarbonyl,    heteroarylaminocarbonyl, C₁₋₄-alkoxycarbonyl,    aryl-C₁₋₃-alkoxycarbonyl, heteroaryl-C₁₋₃-alkoxycarbonyl, amino,    C₁₋₄-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,    pyrrolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-on-1-yl,    morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl,    4-(C₁₋₃-alkyl)piperazin-1-yl, C₁₋₄-alkylcarbonylamino,    arylcarbonylamino, heteroarylcarbonylamino, C₃₋₇-cycloalkyloxy,    C₅₋₇-cycloalkenyloxy, aryloxy, heteroaryloxy, C₁₋₄-alkylsulphinyl,    C₁₋₄-alkylsulphonyl, C₃₋₇-cycloalkylsulphanyl,    C₃₋₇-cycloalkylsulphinyl, C₃₋₇-cycloalkylsulphonyl,    C₅₋₇-cycloalkenylsulphanyl, C₅₋₇-cycloalkenylsulphinyl,    C₅₋₇-cycloalkenylsulphonyl, arylsulphanyl, arylsulphinyl,    arylsulphonyl, heteroarylsulphanyl, heteroarylsulphinyl,    heteroarylsulphonyl, cyano or nitro,    -   while the above-mentioned alkynyl and alkenyl groups may be        mono- or polysubstituted by fluorine or chlorine, and    -   the above-mentioned alkynyl and alkenyl groups may be mono- or        disubstituted by identical or different groups L1, and    -   the above-mentioned cycloalkyl and cycloalkenylrings        independently of one another may be mono- or disubstituted by        substituents selected from fluorine and C₁₋₃-alkyl, and    -   in the above-mentioned cycloalkyl and cycloalkenyl rings one or        two methylene groups may be replaced independently of one        another by O, S, CO, SO, SO₂ or NR^(N),-   B denotes tri-(C₁₋₄-alkyl)silyl-C₁₋₆-alkyl, C₂₋₆-alkyn-1-yl,    C₂₋₆-alken-1-yl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,    pyrrolidin-1-yl, pyrrolidin-2-on-1-yl, piperidin-1-yl,    piperidin-2-on-1-yl, morpholin-4-yl, morpholin-3-on-4-yl,    piperazin-1-yl, 4-(C₁₋₃-alkyl)piperazin-1-yl, arylcarbonylamino,    heteroarylcarbonylamino, nitro, C₃₋₁₀-cycloalkyloxy,    C₅₋₁₀-cycloalkenyloxy, C₃₋₁₀-cycloalkylsulphanyl,    C₃₋₁₀-cycloalkylsulphinyl, C₃₋₁₀-cycloalkylsulphonyl,    C₅₋₁₀-cycloalkenylsulphanyl, C₅₋₁₀-cycloalkenylsulphinyl,    C₅₋₁₀-cycloalkenylsulphonyl, arylsulphanyl, arylsulphinyl,    heteroarylsulphanyl or heteroarylsulphinyl,    -   while the above-mentioned alkynyl and alkenyl groups may be        mono- or polysubstituted by fluorine or chlorine, and    -   the above-mentioned alkynyl and alkenyl groups may be mono- or        disubstituted by identical or different groups L1;    -   while the above-mentioned cycloalkyl and cycloalkenyl rings may        be mono- or disubstituted independently of one another by        substituents selected from fluorine and C₁₋₃-alkyl, and    -   in the above-mentioned cycloalkyl and cycloalkenyl rings one or        two methylene groups may be replaced independently of one        another by O, S, CO, SO, SO₂ or NR^(N),-   R^(N) denotes H, C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl or    C₁₋₄-alkylsulphonyl,-   L1 independently of one another are selected from among hydroxy,    cyano, nitro, C₃₋₇-cycloalkyl, aryl, heteroaryl, C₁₋₄-alkylcarbonyl,    arylcarbonyl, heteroarylcarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,    pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,    C₁₋₄-alkoxycarbonyl, aryl-C₁₋₃-alkoxycarbonyl,    heteroaryl-C₁₋₃-alkoxycarbonyl, C₁₋₄-alkyloxy, aryloxy,    heteroaryloxy, C₁₋₄-alkylsulphanyl, arylsulphanyl,    heteroarylsulphanyl, C₁₋₄-alkylsulphinyl, arylsulphinyl,    heteroarylsulphinyl, C₁₋₄-alkylsulphonyl, arylsulphonyl and    heteroarylsulphonyl; and-   L2 independently of one another are selected from among fluorine,    chlorine, bromine, iodine, C₁₋₃-alkyl, difluoromethyl,    trifluoromethyl, C₁₋₃-alkoxy, difluoromethoxy, trifluoromethoxy and    cyano; and-   R⁶, R^(7a),-   R^(7b), R^(7c) independently of one another have a meaning selected    from among hydrogen, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl,    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups which may be mono- or    disubstituted independently of one another by identical or different    groups L2; and    by the heteroaryl groups mentioned in the definition of the above    groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl,    benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or    tetrazolyl group,    or is meant a pyrrolyl, furanyl, thienyl or pyridyl group, wherein    one or two methyne groups are replaced by nitrogen atoms,    or is meant an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or    isoquinolinyl group, wherein one to three methyne groups are    replaced by nitrogen atoms,    while the above-mentioned heteroaryl groups independently of one    another may be mono- or disubstituted by identical or different    groups L2;    while, unless otherwise stated, the above-mentioned alkyl groups may    be straight-chain or branched,    the tautomers, the stereoisomers thereof, the mixtures thereof and    the salts thereof.

The compounds of general formula I according to the invention and thephysiologically acceptable salts thereof have valuable pharmacologicalproperties, particularly an inhibitory effect on the sodium-dependentglucose cotransporter SGLT, particularly SGLT2. Moreover compoundsaccording to the invention may have an inhibitory effect on thesodium-dependent glucose cotransporter SGLT1. Compared with a possibleinhibitory effect on SGLT1 the compounds according to the inventionpreferably inhibit SGLT2 selectively.

The present invention also relates to the physiologically acceptablesalts of the compounds according to the invention with inorganic ororganic acids.

This invention also relates to pharmaceutical compositions, containingat least one compound according to the invention or a physiologicallyacceptable salt according to the invention, optionally together with oneor more inert carriers and/or diluents.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition which issuitable for the treatment or prevention or diseases or conditions whichcan be influenced by inhibiting the sodium-dependent glucosecotransporter SGLT, particularly SGLT2.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition which issuitable for the treatment of metabolic disorders.

This invention also relates to the use of at least one compoundaccording to the invention or one of the physiologically acceptablesalts thereof for preparing a pharmaceutical composition for inhibitingthe sodium-dependent glucose cotransporter SGLT, particularly SGLT2.

The invention further relates to a process for preparing apharmaceutical composition according to the invention, characterised inthat a compound according to the invention or one of the physiologicallyacceptable salts thereof is incorporated in one or more inert carriersand/or diluents by a non-chemical method.

The present invention also relates to a process for preparing thecompounds of general formula I according to the invention, characterisedin that

a) in order to prepare compounds of general formula I which are definedas hereinbefore and hereinafter,a compound of general formula II

wherein

-   R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be    mono- or polysubstituted by halogen;-   R^(8a), R^(8b),-   R^(8c), R^(8d) independently of one another have one of the meanings    given hereinbefore and hereinafter for the groups R⁶, R^(7a),    R^(7b), R^(7c), denote a benzyl group or a R^(a)R^(b)R^(c)Si group    or a ketal or acetal group, particularly an alkylidene or    arylalkylidene ketal or acetal group, while in each case two    adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclic    ketal or acetal group or a    1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while the    above-mentioned ethylene bridge forms, together with two oxygen    atoms and the two associated carbon atoms of the pyranose ring, a    substituted dioxane ring, particularly a    2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring, and alkyl, aryl    and/or benzyl groups may be mono- or polysubstituted by halogen or    C₁₋₃-alkoxy and benzyl groups may also be substituted by a    di-(C₁₋₃-alkyl)amino group; and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, wherein the aryl or alkyl groups may be    mono- or polysubstituted by halogen;    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups;    and wherein the groups R¹ to R⁵ and R⁶, R^(7a), R^(7b), R^(7c) are    defined as hereinbefore and hereinafter;    is reacted with a reducing agent in the presence of a Lewis or    Brønsted acid, while the any protective groups present are cleaved    simultaneously or subsequently; or    b) in order to prepare compounds of general formula I wherein R⁶,    R^(7a), R^(7b) and R^(7c) denote hydrogen,    a compound of general formula III

wherein R^(8a), R^(8b), R^(8c), R^(8d) and R¹ to R⁵ are defined ashereinbefore and hereinafter, but at least one of the groups R^(8a),R^(8b), R^(8c), R^(8d) does not denote hydrogen, is hydrolysed, andif desired a compound of general formula I thus obtained wherein R⁶denotes a hydrogen atom, is converted by acylation into a correspondingacyl compound of general formula I, and/orif necessary any protective group used in the reactions described aboveis cleaved and/orif desired a compound of general formula I thus obtained is resolvedinto its stereoisomers and/orif desired a compound of general formula I thus obtained is convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts thereof.

This invention further relates to a process for preparing compounds ofgeneral formula II

wherein

-   R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be    mono- or polysubstituted by halogen;-   R^(8a), R^(8b),-   R^(8c), R^(8d) independently of one another has one of the meanings    given for the groups R⁶, R^(7a), R^(7b), R^(7c), denote a benzyl    group or a R^(a)R^(b)R^(c)Si group or a ketal or acetal group, while    in each case two adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may    form a cyclic ketal or acetal group or may form, with two oxygen    atoms of the pyranose ring, a substituted 2,3-oxydioxane ring,    particularly a 2,3-dimethyl-2,3-di(C₁₋₃-alkoxy)-1,4-dioxane ring,    and alkyl, aryl and/or benzyl groups may be mono- or polysubstituted    by halogen or C₁₋₃-alkoxy and benzyl groups may also be substituted    by a di-(C₁₋₃-alkyl)amino group; and-   R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl,    aryl or aryl-C₁₋₃-alkyl, while the alkyl or aryl groups may be mono-    or polysubstituted by halogen;    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, preferably phenyl    groups;    and R¹ to R⁵, R⁶, R^(7a), R^(7b), R^(7c) are defined as hereinbefore    and hereinafter,    wherein an organometallic compound (V) which may be obtained by    halogen-metal exchange or by inserting a metal in the carbon-halogen    bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R⁵ are defined ashereinbefore and hereinafter, and optionally subsequenttransmetallation, is added to a gluconolactone of general formula VI

wherein R^(8a), R^(8b), R^(8c), R^(8d) are defined as hereinbefore andhereinafter, andthen the resulting adduct, is reacted, preferably in situ, with water oran alcohol R′—OH, while R′ denotes optionally substituted C₁₋₄-alkyl, inthe presence of an acid, such as for example methanesulphonic acid,sulphuric acid, hydrochloric acid, acetic acid or ammonium chloride, andoptionally the product obtained in the reaction with water wherein R′denotes H is converted, in a subsequent reaction, with an acylatingagent, such as for example the corresponding acid chloride or anhydride,into the product of formula II wherein R′ denotes (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C₁₋₃-alkyl)-carbonyl,which may be substituted as specified.

The intermediate products listed, particularly those of formula IV,formula II and formula III, are also a subject of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly R¹ to R⁵, A, B, L1, L2, R^(N), R⁶, R^(7a), R^(7b), R^(7c),R^(8a), R^(8b), R^(8c), R^(8d), are defined as above and hereinafter.

If residues, substituents or groups occur several times in a compound,they may have the same or different meanings.

According to the invention preferred glucopyranosyl-substituted benzenederivatives are those of general formula I

wherein

-   R¹ is selected from the definitions of the group A and    -   if R³ is selected from the definitions of the group B, R¹ may        additionally also be selected from the meanings hydrogen,        fluorine, chlorine, bromine, iodine, C₁₋₄-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkyl, C₂₋₄-alkynyl-C₁₋₄-alkyl,        C₃₋₇-cycloalkyl-C₁₋₄-alkyl, C₅₋₇-cycloalkenyl-C₁₋₄-alkyl, a        methyl group substituted by 1 to 3 fluorine atoms, an ethyl        group substituted by 1 to 5 fluorine atoms, C₁₋₄-alkoxy, a        methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy        group substituted by 1 to 5 fluorine atoms, a C₁₋₄-alkyl group        substituted by a hydroxy or C₁₋₃-alkoxy group, a C₂₋₄-alkoxy        group substituted by a hydroxy or C₁₋₃-alkoxy group,        C₃₋₆-cycloalkyl-C₁₋₃-alkoxy or hydroxy,    -   while in the above-mentioned cycloalkyl and cycloalkenyl rings        one or two methylene groups may be replaced independently of one        another by O or CO, and-   R² denotes hydrogen, fluorine, chlorine, bromine, hydroxy,    C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano or nitro, while the alkyl or alkoxy    group may be mono- or polysubstituted by fluorine, and-   R³ is selected from the definitions of the group B and    -   if R¹ is selected from the definitions of the group A, R³ may        additionally also be selected from the meanings hydrogen,        fluorine, chlorine, bromine, iodine, C₁₋₆-alkyl,        C₂₋₄-alkenyl-C₁₋₄-alkyl, C₂₋₄-alkynyl-C₁₋₄-alkyl,        C₃₋₇-cycloalkyl, C₅₋₇-cycloalkenyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl,        C₆₋₇-cycloalkenyl-C₁₋₄-alkyl, C₃₋₆-cycloalkylidenemethyl,        hydroxy, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₃-alkoxy, aryl,        aryl-C₁₋₃-alkyl, heteroaryl, heteroaryl-C₁₋₃-alkyl, aryloxy,        aryl-C₁₋₃-alkyl-oxy, a methyl or methoxy group substituted by 1        to 3 fluorine atoms, a C₂₋₄-alkyl or C₂₋₄-alkoxy group        substituted by 1 to 5 fluorine atoms, a C₁₋₄-alkyl group        substituted by a cyano group, a C₁₋₄-alkyl group substituted by        a hydroxy or C₁₋₃-alkyloxy group, cyano, carboxy,        C₁₋₃-alkoxycarbonyl, aminocarbonyl, (C₁₋₃-alkylamino)carbonyl,        di-(C₁₋₃-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl,        piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl,        (C₁₋₄-alkyl)carbonylamino, C₁₋₄-alkylsulphonylamino,        C₁₋₄-alkylsulphanyl, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,        arylsulphonylamino, aryl-C₁₋₃-alkylsulphonylamino or        arylsulphonyl,-   R⁴, R⁵ independently of one another denote hydrogen, fluorine,    chlorine, bromine, iodine, cyano, nitro, C₁₋₃-alkyl, C₁₋₃-alkoxy,    methyl or methoxy substituted by 1 to 3 fluorine atoms,-   A denotes C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl, C₃₋₇-cycloalkyl,    C₅₋₇-cycloalkenyl, aryl, heteroaryl, C₁₋₄-alkylcarbonyl,    arylcarbonyl, heteroarylcarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,    pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,    4-(C₁₋₄-alkyl)piperazin-1-ylcarbonyl, arylaminocarbonyl,    heteroarylaminocarbonyl, C₁₋₄-alkoxycarbonyl,    aryl-C₁₋₃-alkoxycarbonyl, heteroaryl-C₁₋₃-alkoxycarbonyl, amino,    C₁₋₄-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,    pyrrolidin-2-on-1-yl, piperidin-1-yl, piperidin-2-on-1-yl,    morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl,    4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₄-alkylcarbonylamino,    arylcarbonylamino, heteroarylcarbonylamino, C₃₋₇-cycloalkyloxy,    C₅₋₇-cycloalkenyloxy, aryloxy, heteroaryloxy, C₁₋₄-alkylsulphinyl,    C₁₋₄-alkylsulphonyl, C₃₋₇-cycloalkylsulphanyl,    C₃₋₇-cycloalkylsulphinyl, C₃₋₇-cycloalkylsulphonyl,    C₅₋₇-cycloalkenylsulphanyl, C₅₋₇-cycloalkenylsulphinyl,    C₅₋₇-cycloalkenylsulphonyl, arylsulphanyl, arylsulphinyl,    arylsulphonyl, heteroarylsulphanyl, heteroarylsulphinyl,    heteroarylsulphonyl, cyano or nitro,    -   while the above-mentioned alkynyl- and alkenyl groups may be        mono- or polysubstituted by fluorine or chlorine, and    -   while the above-mentioned alkynyl and alkenyl groups may be        mono- or disubstituted by identical or different groups L1, and    -   the above-mentioned cycloalkyl and cycloalkenyl rings may be        mono- or disubstituted independently of one another by        substituents selected from fluorine and C₁₋₃-alkyl, and    -   in the above-mentioned cycloalkyl and cycloalkenyl rings one or        two methylene groups may be replaced independently of one        another by O, S, CO, SO, SO₂ or NR^(N),-   B denotes tri-(C₁₋₄-alkyl)silyl-C₁₋₆-alkyl, C₂₋₆-alkyn-1-yl,    C₂₋₆-alken-1-yl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,    pyrrolidin-1-yl, pyrrolidin-2-on-1-yl, piperidin-1-yl,    piperidin-2-on-1-yl, morpholin-4-yl, morpholin-3-on-4-yl,    piperazin-1-yl, 4-(C₁₋₃-alkyl)piperazin-1-yl, arylcarbonylamino,    heteroarylcarbonylamino, nitro, C₃₋₇-cycloalkyloxy,    C₅₋₇cycloalkenyloxy, C₃₋₇-cycloalkylsulphanyl,    C₃₋₇-cycloalkylsulphinyl, C₃₋₇-cycloalkylsulphonyl,    C₅₋₇-cycloalkenylsulphanyl, C₅₋₇-cycloalkenylsulphinyl,    C₅₋₇-cycloalkenylsulphonyl, arylsulphanyl, arylsulphinyl,    heteroarylsulphanyl or heteroarylsulphinyl, while the    above-mentioned alkynyl and alkenyl groups may be mono- or    polysubstituted by fluorine or chlorine, and    -   the above-mentioned alkynyl and alkenyl groups may be mono- or        disubstituted by identical or different groups L1;    -   the above-mentioned cycloalkyl and cycloalkenyl rings may be        mono- or disubstituted independently of one another by        substituents selected from fluorine and C₁₋₃-alkyl, and    -   in the above-mentioned cycloalkyl and cycloalkenyl rings one or        two methylene groups may be replaced independently of one        another by O, S, CO, SO, SO₂ or NR^(N),-   R^(N) denotes H or C₁₋₄-alkyl,-   L1 independently of one another are selected from among cyano,    nitro, aryl, heteroaryl, C₁₋₄-alkylcarbonyl, arylcarbonyl,    heteroarylcarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl,    piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl,    heteroarylaminocarbonyl, C₁₋₄-alkoxycarbonyl,    aryl-C₁₋₃-alkoxycarbonyl, heteroaryl-C₁₋₃-alkoxycarbonyl,    C₁₋₄-alkyloxy, aryloxy, heteroaryloxy, C₁₋₄-alkylsulphanyl,    arylsulphanyl, heteroarylsulphanyl, C₁₋₄-alkylsulphinyl,    arylsulphinyl, heteroarylsulphinyl, C₁₋₄-alkylsulphonyl,    arylsulphonyl and heteroarylsulphonyl; and-   L2 independently of one another are selected from among fluorine,    chlorine, bromine, iodine, C₁₋₃-alkyl, difluoromethyl,    trifluoromethyl, C₁₋₃-alkoxy, difluoromethoxy, trifluoromethoxy and    cyano; and-   R⁶, R^(7a),-   R^(7b), R^(7c) independently of one another have a meaning selected    from among hydrogen, (C₁₋₁₈-alkyl)carbonyl,    (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and    aryl-(C₁₋₃-alkyl)-carbonyl,    while by the aryl groups mentioned in the definition of the above    groups are meant phenyl or naphthyl groups, which may be mono- or    disubstituted independently of one another by identical or different    groups L2; and    by the heteroaryl groups mentioned in the definition of the above    groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl,    benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group,    or is meant a pyrrolyl, furanyl, thienyl or pyridyl group, wherein    one or two methyne groups are replaced by nitrogen atoms,    or is meant an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or    isoquinolinyl group, wherein one to three methyne groups are    replaced by nitrogen atoms,    while the above-mentioned heteroaryl groups may be mono- or    disubstituted independently of one another by identical or different    groups L2;    while, unless otherwise stated, the above-mentioned alkyl groups may    be straight-chain or branched,    the tautomers, the stereoisomers thereof, the mixtures thereof and    the salts thereof.

Some preferred meanings of individual groups and substituents of thecompounds according to the invention will be given hereinafter.

The group R³ is preferably in the meta or para position to the —CH₂bridge, so that compounds according to the following formulae I.1 andI.2, particularly formula I.2, are preferred:

The term aryl appearing in the groups L1, R¹, R³, A and B preferablydenotes phenyl.

The term heteroaryl occurring in the groups L1, R¹, R³, A and Bpreferably denotes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, thiazolyl or thiadiazolyl.

The group A preferably denotes C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl,C₃₋₇-cycloalkyl, C₅₋₇-cycloalkenyl, C₁₋₄-alkylcarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,piperazin-1-ylcarbonyl, 4-(C₁₋₄-alkyl)piperazin-1-ylcarbonyl,C₁₋₄-alkoxycarbonyl, amino, C₁₋₄-alkylamino, di-(C₁₋₃-alkyl)amino,pyrrolidin-1-yl, pyrrolidin-2-on-1-yl, piperidin-1-yl,piperidin-2-on-1-yl, morpholin-4-yl, morpholin-3-on-4-yl,piperazin-1-yl, 4-(C₁₋₃-alkyl)piperazin-1-yl, C₁₋₄-alkylcarbonylamino,C₃₋₇-cycloalkyloxy, C₅₋₇-cycloalkenyloxy, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, C₃₋₇-cycloalkylsulphanyl, C₃₋₇-cycloalkylsulphinyl,C₃₋₇-cycloalkylsulphonyl, C₅₋₇-cycloalkenylsulphanyl,C₅₋₇-cycloalkenylsulphinyl, C₅₋₇-cycloalkenylsulphonyl, cyano and nitro,

while the above-mentioned alkynyl and alkenyl groups may be mono- orpolysubstituted by fluorine or chlorine, preferably fluorine, andthe above-mentioned alkynyl and alkenyl groups may be mono- ordisubstituted by identical or different groups L1, andthe above-mentioned cycloalkyl and cycloalkenyl rings may be mono- ordisubstituted independently of one another by substituents selected fromfluorine and C₁₋₃-alkyl, andin the above-mentioned cycloalkyl and cycloalkenyl rings one or twomethylene groups may be replaced independently of one another by O, S,CO, SO, SO₂ or NR^(N), preferably O or CO, most particularly preferablyby O.

Particularly preferably, the group A denotes C₂₋₆-alkyn-1-yl,C₂₋₆-alken-1-yl, C₃₋₇-cycloalkyl, C₅₋₇-cycloalkenyl, C₃₋₇-cycloalkyloxy,C₅₋₇-cycloalkenyloxy, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,C₃₋₇-cycloalkylsulphanyl, C₃₋₇-cycloalkylsulphinyl,C₃₋₇-cycloalkylsulphonyl, C₅₋₇-cycloalkenylsulphanyl,C₅₋₇-cycloalkenylsulphinyl, C₅₋₇-cycloalkenylsulphonyl, cyano and nitro,

while the above-mentioned alkynyl and alkenyl groups may be mono- orpolysubstituted by fluorine or chlorine, preferably fluorine, andthe above-mentioned alkynyl and alkenyl groups may be mono- ordisubstituted by identical or different groups L1, andthe above-mentioned cycloalkyl and cycloalkenyl rings may be mono- ordisubstituted independently of one another by substituents selected fromfluorine and C₁₋₃-alkyl, andin the above-mentioned C₅₋₆-cycloalkyl rings a methylene group may bereplaced by O.

Most particularly preferably, the group A denotes C₂₋₆-alkyn-1-yl,C₂₋₆-alken-1-yl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyloxy, cyano, while inC₅₋₆-cycloalkyl groups a methylene unit may be replaced by O.

Examples of the most particularly preferred definitions of the group Aare ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, cyano, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

The group B preferably denotes tri-(C₁₋₄-alkyl)silyl-C₁₋₆-alkyl,C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, pyrrolidin-2-on-1-yl,piperidin-1-yl, piperidin-2-on-1-yl, morpholin-4-yl,morpholin-3-on-4-yl, piperazin-1-yl, 4-(C₁₋₃-alkyl)piperazin-1-yl,nitro, C₃₋₇-cycloalkyloxy, C₅₋₇-cycloalkenyloxy,C₃₋₇-cycloalkylsulphanyl, C₃₋₇-cycloalkylsulphinyl,C₃₋₇-cycloalkylsulphonyl, C₅₋₇-cycloalkenylsulphanyl,C₅₋₇-cycloalkenylsulphinyl, C₅₋₇-cycloalkenylsulphonyl,

while the above-mentioned alkynyl and alkenyl groups may be mono- orpolysubstituted by fluorine or chlorine, preferably fluorine, andthe above-mentioned alkynyl and alkenyl groups may be mono- ordisubstituted by identical or different groups L1;the above-mentioned cycloalkyl and cycloalkenyl rings may be mono- ordisubstituted independently of one another by substituents selected fromfluorine and C₁₋₃-alkyl, andin the above-mentioned cycloalkyl and cycloalkenyl rings one or twomethylene groups may be replaced independently of one another by O, S,CO, SO, SO₂ or NR^(N), preferably O, CO, S, SO₂ or NR^(N), mostparticularly preferably by O or CO.

Particularly preferably the group B denotestri-(C₁₋₄-alkyl)silyl-C₁₋₆-alkyl, C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl,nitro, C₃₋₇-cycloalkyloxy, C₅₋₇-cycloalkenyloxy,C₃₋₇-cycloalkylsulphanyl, C₃₋₇-cycloalkylsulphinyl,C₃₋₇-cycloalkylsulphonyl, C₅₋₇-cycloalkenylsulphanyl,C₅₋₇-cycloalkenylsulphinyl, C₅₋₇-cycloalkenylsulphonyl, while theabove-mentioned alkynyl and alkenyl groups may be mono- orpolysubstituted by fluorine or chlorine, preferably fluorine, and

the above-mentioned alkynyl and alkenyl groups may be mono- ordisubstituted by identical or different groups L1;while the above-mentioned cycloalkyl and cycloalkenyl rings may be mono-or disubstituted independently of one another by substituents selectedfrom fluorine and C₁₋₃-alkyl, andin the above-mentioned cycloalkyl and cycloalkenyl rings one or twomethylene groups may be replaced independently of one another by O, S,CO, SO, SO₂ or NR^(N), preferably O, CO, S, SO₂ or NR^(N), mostparticularly preferably by O or CO.

Most particularly preferably the group B denotestri-(C₁₋₄-alkyl)silyl-C₁₋₆-alkyl, C₂₋₆-alkyn-1-yl, C₂₋₆-alken-1-yl,C₃₋₇-cycloalkyloxy, C₅₋₇-cycloalkenyloxy, C₃₋₇-cycloalkylsulphanyl,C₅₋₇-cycloalkenylsulphanyl, while the above-mentioned alkynyl andalkenyl groups may be mono- or polysubstituted by fluorine ormonosubstituted by chlorine or the group L1, and in the cycloalkyl andcycloalkenyl groups one or two methylene groups may be replacedindependently of one another by O, CO, S, SO₂ or NR^(N), particularly Oor CO.

Examples of most particularly preferred definitions of the group B aretrimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl,tert.-butylethynyl, 2-hydroxyprop-2-ylethynyl,2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl,3-methoxy-1-propyn-1-yl, ethenyl, 1-propenyl, 1-butenyl,tert.-butylethenyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy,1,1-dioxotetrahydrothiophenyloxy, tetrahydropyranyloxy,tetrahydrothiopyranyloxy, 1,1-dioxotetrahydrothiopyranyloxy,tetrahydrofuranonyloxy, piperidinyloxy, piperidinonyloxy,pyrrolidin-3-yloxy, pyrrolidinon-3-yloxy, tetrahydrofuranyl-sulphanyl,cyclopropylsulphanyl, cyclobutylsulphanyl, cyclopentylsulphanyl andcyclohexylsulphanyl, while the —NH group in a piperidinyl,piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring may be substituted byR^(N), particularly C₁₋₃-alkyl or acetyl.

Most particularly preferred meanings are trimethylsilylethyl, ethynyl,2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl,3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxyand N-acetylpiperidin-4-yloxy. Examples which deserve special mentionare ethynyl, trimethylsilylethyl, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, tetrahydrofuran-3-yloxy and tetrahydropyran-4-yloxy.

If in the residues or groups A, B, R¹ or R³ there are cycloalkyl orcycloalkenyl rings wherein two methylene groups are replaced by O, S orNR^(N) or are replaced by S, NR^(N), CO, SO or SO₂, these methylenegroups are preferably not directly connected to one another. If howevertwo methylene groups are replaced by O and CO or by NR^(N) and CO, thesemay be directly connected to one another, so as to form a —O—CO— or—NR^(N)—CO group.

Preferred meanings of the group L1 are selected from among hydroxy,cyano, C₃₋₆-cycloalkyl, C₁₋₄-alkylcarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₃-alkyl)aminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkyloxy, C₁₋₄-alkylsulphanyl,C₁₋₄-alkylsulphinyl, and C₁₋₄-alkylsulphonyl.

Particularly preferred meanings of the group L1 are selected from amonghydroxy, C₁₋₄-alkyloxy and C₁₋₄-alkylsulphanyl.

If L1 denotes hydroxy, the hydroxy group is not directly linked to a Catom of a double or triple bond.

Compounds according to a first embodiment of this invention may bedescribed by general formula I, particularly formulae I.1 and I.2,particularly preferably formula I.2, wherein

-   R³ is selected from one of the definitions of the group B given    hereinbefore and    the other groups and substituents are defined as hereinbefore and    hereinafter,    including the tautomers, the stereoisomers thereof, the mixtures    thereof and the salts thereof.

According to this embodiment preferred meanings of the group R¹ arehydrogen, fluorine, chlorine, bromine, iodine, C₁₋₄-alkyl, C₂₋₆-alkynyl,C₁₋₄-alkoxy, C₂₋₄-alkenyl-C₁₋₄-alkoxy, C₂₋₄-alkynyl-C₁₋₄-alkoxy, methylsubstituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxysubstituted by 1 to 5 fluorine atoms, C₁₋₄-alkyl substituted by ahydroxy or C₁₋₃-alkoxy group, C₂₋₄-alkoxy substituted by a hydroxy orC₁₋₃-alkoxy group, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₇-cycloalkyloxy,C₃₋₆-cycloalkyl-C₁₋₃-alkoxy, C₅₋₇-cycloalkenyloxy, hydroxy, amino, nitroor cyano, while in the C₅₋₆-cycloalkyl groups a methylene group may bereplaced by 0.

Particularly preferred meanings are hydrogen, fluorine, chlorine,bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl,trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy,methoxy, ethoxy, difluoromethoxy, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, particularly methyl and chlorine.

Compounds according to a second embodiment of this invention may bedescribed by general formula I, particularly formulae I.1 and I.2,particularly preferably formula I.2, wherein

-   R¹ is selected from the definitions of the group A given    hereinbefore and    the other groups and substituents are defined as hereinbefore and    hereinafter,    including the tautomers, the stereoisomers thereof, the mixtures    thereof and the salts thereof.

According to this second embodiment preferred meanings of the group R³are hydrogen, fluorine, chlorine, bromine, hydroxy, cyano, C₁₋₆-alkyl,trimethylsilylethyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, difluoromethyl,trifluoromethyl, C₃₋₇-cycloalkyl, C₅₋₇-cycloalkenyl, C₁₋₆-alkyloxy,difluoromethoxy, trifluoromethoxy, pentafluorethoxy, C₃₋₇-cycloalkyloxy,tetrahydrofuranyloxy, tetrahydrofuranonyloxy, C₁₋₆-alkylsulphanyl,cyclopropylidenemethyl, aryl or heteroaryl.

According to this second embodiment particularly preferred meanings ofthe group R³ are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,tert.-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl,trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy,isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy,pentafluorethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy,methylsulphanyl, ethylsulphanyl, isopropylsulphanyl,cyclopropylidenemethyl, phenyl, fluorophenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl.

According to this second embodiment most particularly preferred meaningsof the group R³ are hydrogen, fluorine, chlorine, methyl, ethyl,isopropyl, tert.-butyl, ethynyl, 1-propynyl, trimethylsilylethyl,difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,methoxy, ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy,trifluoromethoxy, pentafluorethoxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-on-3-yloxy, methylsulphanyl, ethylsulphanyl,isopropylsulphanyl, cyclopropylidenemethyl. Examples of suchparticularly preferred meanings are methyl, ethyl, methoxy, ethoxy,trimethylsilylethyl, ethynyl, cyclopentyloxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-on-3-yloxy, particularly trimethylsilylethyl, ethoxy,cyclopentyloxy and tetrahydrofuran-3-yloxy.

Meanings of other groups and substituents will now be given which are tobe regarded as preferred according to general formula I, formulae I.1and I.2 and also according to the embodiments described hereinbefore:

Preferred meanings of the group R² are hydrogen, fluorine, chlorine,bromine, methyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, cyano,nitro and methyl substituted by 1 to 3 fluorine atoms.

Particularly preferred meanings of the group R² are hydrogen, fluorine,hydroxy, methoxy, ethoxy and methyl, particularly hydrogen and methyl.

Preferred meanings of the group R⁴ are hydrogen and fluorine,particularly hydrogen.

Preferred meanings of the group R⁵ are hydrogen and fluorine,particularly hydrogen. The group R^(N) preferably denotes H, methyl,ethyl or acetyl.

The group R⁶ preferably denotes according to the invention hydrogen,(C₁₋₈-alkyl)oxycarbonyl, C₁₋₈-alkylcarbonyl or benzoyl, particularlyhydrogen or (C₁₋₆-alkyl)oxycarbonyl, C₁₋₆-alkylcarbonyl, particularlypreferably hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl,most particularly preferably hydrogen or methoxycarbonyl.

The substituents R^(7a), R^(7b), R^(7c) preferably representindependently of one another hydrogen, (C₁₋₈-alkyl)oxycarbonyl,(C₁₋₁₈-alkyl)carbonyl, benzoyl, particularly hydrogen or(C₁₋₆-alkyl)oxycarbonyl, (C₁₋₈-alkyl)carbonyl, particularly preferablyhydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl orethylcarbonyl. Most particularly preferably R^(7a), R^(7b) and R^(7c)represent hydrogen.

The compounds of formula I wherein R⁶, R^(7a), R^(7b) and R^(7c)according to the invention have a meaning other than hydrogen, forexample C₁₋₈-alkylcarbonyl, are preferably suitable as intermediateproducts for the synthesis of compounds of formula I wherein R^(7a),R^(7b) and R^(7c) denote hydrogen.

Particularly preferred compounds of general formula I are selected fromamong formulae I.2a to I.2d, particularly I.2c:

while the groups R¹ to R⁶ and R^(7a), R^(7b), R^(7c) have one of themeanings given previously, particularly have one of the meanings givenspecified as being preferred; and particularly

-   R¹ denotes hydrogen, fluorine, chlorine, bromine, iodine,    C₁₋₄-alkyl, C₂₋₆-alkynyl, C₁₋₄-alkoxy, C₂₋₄-alkenyl-C₁₋₄-alkoxy,    C₂₋₄-alkynyl-C₁₋₄-alkoxy, methyl substituted by 1 to 3 fluorine    atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy    substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5    fluorine atoms, C₁₋₄-alkyl substituted by a hydroxy or C₁₋₃-alkoxy    group, C₂₋₄-alkoxy substituted by a hydroxy or C₁₋₃-alkoxy group,    C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,    C₃₋₇-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkoxy,    C₅₋₇-cycloalkenyloxy, hydroxy, amino, nitro or cyano, while in the    C₅₋₆-cycloalkyl groups a methylene group may be replaced by O;    particularly preferably denotes hydrogen, fluorine, chlorine,    bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl,    trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy,    methoxy, ethoxy, difluoromethoxy, cyclopropyloxy, cyclobutyloxy,    cyclopentyloxy or cyclohexyloxy; and-   R² denotes hydrogen, fluorine, hydroxy, methoxy, ethoxy or methyl,    particularly hydrogen or methyl; and-   R³ is selected from the group B consisting of trimethylsilylethyl,    ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert.-butylethynyl,    2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl,    3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, ethenyl,    1-propenyl, 1-butenyl, tert.-butylethenyl, cyclopropyloxy,    cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyloxy,    tetrahydrothiophenyloxy, 1,1-dioxotetrahydrothiophenyloxy,    tetrahydropyranyloxy, tetrahydrothiopyranyloxy,    1,1-dioxotetrahydrothiopyranyloxy, tetrahydrofuranonyloxy,    piperidinyloxy, piperidinonyloxy, pyrrolidin-3-yloxy,    pyrrolidinone-3-yloxy, tetrahydrofuranyl-sulphanyl,    cyclopropylsulphanyl, cyclobutylsulphanyl, cyclopentylsulphanyl and    cyclohexylsulphanyl, while the —NH group in a piperidinyl,    piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring may be    substituted by R^(N), particularly C₁₋₃-alkyl or acetyl; is    particularly preferably selected from trimethylsilylethyl, ethynyl,    2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl,    3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropyloxy,    cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,    tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy,    N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy; and-   R⁴ denotes hydrogen or fluorine, particularly hydrogen; and-   R⁵ denotes hydrogen or fluorine, particularly hydrogen; and-   R⁶ denotes hydrogen, (C₁₋₆-alkyl)oxycarbonyl, (C₁₋₆-alkyl)carbonyl    or benzoyl, particularly hydrogen, methylcarbonyl, methoxycarbonyl    or ethoxycarbonyl, most particularly preferably hydrogen; and-   R^(7a), R^(7b), R^(7c) independently of one another represent    hydrogen, (C₁₋₆-alkyl)oxycarbonyl, (C₁₋₈-alkyl)carbonyl or benzoyl,    particularly hydrogen, methoxycarbonyl, ethoxycarbonyl,    methylcarbonyl or ethylcarbonyl, particularly preferably hydrogen;    including the tautomers, the stereoisomers, the mixtures thereof and    the salts thereof.

According to a variant of the embodiments given hereinbefore, otherpreferred compounds are those wherein the phenyl group which carries thesubstituent R³ has at least one other substituent R⁴ and/or R⁵ which isdifferent from hydrogen. According to this variant, particularlypreferred compounds are those which have a substituent R⁴ representingfluorine.

The phenyl group which carries the substituent R³ is preferably at mostmonofluorinated.

The compounds of general formula I specified in the experimental sectionthat follows, and the derivatives thereof, wherein R⁶ has a meaningaccording to the invention other than hydrogen, particularly wherein R⁶denotes ethoxycarbonyl or methoxycarbonyl, including the tautomers, thestereoisomers thereof and the mixtures thereof, are preferred accordingto the invention.

Particularly preferred compounds of general formula I are selected fromamong:

-   (1)    1-chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzene-   (2)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene-   (3)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene-   (4)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydrofuran-2-on-3-yloxy)-benzyl]-benzene-   (5)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclobutyloxy-benzyl)-benzene-   (6)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzene-   (7)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydropyran-4-yloxy)-benzyl]-benzene-   (8)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-acetyl-piperidin-4-yloxy)-benzyl]-benzene-   (10)    1-(β-D-Glucopyranos-1-yl)-4-methyl-3-[4-(tetrahydrofuran-3-yloxy)-benzyl]-benzene-   (11)    1-(β-D-Glucopyranos-1-yl)-4-methyl-3-[4-(2-trimethylsilyl-ethyl)-benzyl]-benzene-   (12) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene-   (13)    1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(piperidin-4-yloxy)-benzyl]-benzene-   (14) 1-fluoro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene-   (15) 1-(β-D-glucopyranos-1-yl)-3-(4-ethynyl-benzyl)-benzene-   (16) 1-ethynyl-4-(β-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzene-   (17)    1-methoxy-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene    and the derivatives thereof wherein R⁶ has a meaning according to    the invention other than hydrogen, particularly wherein R⁶ denotes    ethoxycarbonyl or methoxycarbonyl,    including the tautomers, the stereoisomers thereof and the mixtures    thereof.

In the processes according to the invention the groups R¹, R², R³, R⁴and R⁵ preferably have the meanings specified hereinbefore as beingpreferred. Moreover R′ preferably denotes H, C₁₋₃-alkyl or benzyl,particularly H, ethyl or methyl. The groups R^(8a), R^(8b), R^(8c) andR^(8d) independently of one another preferably denote H,C₁₋₄-alkylcarbonyl or benzyl, particularly H, methylcarbonyl,ethylcarbonyl or benzyl.

The invention also relates to compounds of general formula IV,particularly of general formula IV′

wherein Hal denotes chlorine, bromine or iodine and the groups R¹, R²,R⁴ and R⁵ are as hereinbefore defined and the group R³ is selected fromthe group B, as intermediate products or starting materials in thesynthesis of the compounds according to the invention. Particularlypreferably, the groups R¹, R², R³, R⁴ and R⁵ have the meanings givenafter formulae I.2a to I.2d. Most particularly preferred are compoundsof general formula IV′, wherein Hal denotes chlorine, bromine or iodineand the groups R¹, R², R⁴ and R⁵ have the meanings given after formulaeI.2a to I.2d and the group R³ denotes ethynyl or C₃₋₆-1-alkyn-1-yl,while the ethynyl group may be substituted by the group —SiR₃, while thegroups R independently of one another represent C₁₋₄-alkyl, C₁₋₄-alkoxyor aryl, and the C₃₋₆-1-alkyn-1-yl group may be substituted by hydroxyor C₁₋₃-alkoxy, particularly hydroxy or methoxy.

The invention also relates to compounds of general formula II,particularly of general formula II′

wherein R′, R^(8a), R^(8b), R^(8c), R^(8d), R¹, R², R³, R⁴ and R⁵ aredefined as hereinbefore and hereinafter; particularly wherein R′ denotesH, C₁₋₃-alkyl or benzyl, particularly H, ethyl or methyl; and the groupsR^(8a), R^(8b), R^(8c) and R^(8d) independently of one another representH, C₁₋₄-alkylcarbonyl or benzyl, particularly H, methylcarbonyl,ethylcarbonyl or benzyl and the groups R¹, R², R⁴ and R⁵ are ashereinbefore defined and the group R³ is selected from the group B, asintermediate products or starting materials in the synthesis of thecompounds according to the invention. Particularly preferably the groupsR¹, R², R³, R⁴ and R⁵ have the meanings given following formulae I.2a toI.2d.

Some terms used above and hereinafter to describe the compoundsaccording to the invention will now be defined more closely.

The term halogen denotes an atom selected from the group consisting ofF, Cl, Br and I, particularly F, Cl and Br.

The term C_(1-n)-alkyl, wherein n may have a value of 1 to 18, denotes asaturated, branched or unbranched hydrocarbon group with 1 to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, iso-propyl,butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C_(2-n)-alkynyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a CCtriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl etc. Unless otherwise stated alkynyl groups are connected tothe remainder of the molecule via the C atom in position 1.

Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. areequivalent to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc.This also applies analogously to C_(2-n)-alkenyl groups.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-O group, whereinC_(1-n)-alkyl is as hereinbefore defined. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,tert-pentoxy, n-hexoxy, iso-hexoxy etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl-C(═O) group,wherein C_(1-n)-alkyl is as hereinbefore defined. Examples of suchgroups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri- orspirocarbocyclic group with 3 to n C atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl,spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.Preferably the term C₃₋₇-cycloalkyl denotes saturated monocyclic groups.

The term C_(5-n)-cycloalkenyl denotes a C_(5-n)-cycloalkyl group whichis as hereinbefore defined and additionally has at least one unsaturatedC═C double bond.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group wherein C_(3-n)-cycloalkyl is as hereinbefore defined.

The term tri-(C₁₋₄-alkyl)silylcomprises silyl groups which haveidentical or two or three different alkyl groups.

The term di-(C₁₋₃-alkyl)amino comprises amino groups which haveidentical or two different alkyl groups.

The style used above and hereinafter, in which a bond of a substituentin a phenyl group is shown towards the centre of the phenyl ring,denotes, unless otherwise stated, that this substituent may be bound toany free position of the phenyl ring bearing an H atom.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

The glucose derivatives of formula II according to the invention may besynthesised from D-gluconolactone or a derivative thereof by adding thedesired benzylbenzene compound in the form of an organometallic compound(Diagram 1).

Diagram 1: Addition of an Organometallic Compound to a Gluconolactone

The reaction according to Diagram 1 is preferably carried out startingfrom a halo-benzylbenzene compound of general formula IV, wherein Haldenotes chlorine, bromine or iodine. Starting from the haloaromaticcompound IV the corresponding organometallic compound (V) may beprepared either by means of a so-called halogen-metal exchange or byinserting the metal into the carbon-halogen bond. The halogen-metalexchange with bromine or iodine-substituted aromatic groups may becarried out for example with an organolithium compound such as e.g. n-,sec- or tert-butyllithium and thereby yields the corresponding lithiatedaromatic group. The analogous magnesium compound may also be generatedby a halogen-metal exchange with a suitable Grignard compound such ase.g. isopropylmagnesium bromide or diisopropylmagnesium. The reactionsare preferably carried out between 0 and −100° C., particularlypreferably between −10 and −80° C., in an inert solvent or mixturesthereof, such as for example diethyl ether, tetrahydrofuran, toluene,hexane or methylene chloride. The magnesium or lithium compounds thusobtained may optionally be transmetallised with metal salts such as e.g.cerium trichloride, to form additional organometallic compounds (V)suitable for addition. Alternatively the organometallic compound (V) mayalso be prepared by inserting a metal into the carbon-halogen bond ofthe haloaromatic compound IV. Metals such as e.g. lithium or magnesiumare suitable for this. The addition of the organometallic compound V togluconolactone or derivatives thereof of formula VI is preferablycarried out at temperatures between 0 and −100° C., particularlypreferably at −30 to −80° C., in an inert solvent or mixtures thereof,to obtain the compound of formula II. The lithiation and/or couplingreaction may also be carried out in microreactors and/or micromixers inorder to avoid low temperatures; for example analogously to theprocesses described in WO 2004/076470.

Suitable solvents are e.g. diethyl ether, toluene, methylene chloride,hexane, tetrahydrofuran or mixtures thereof. The reactions may becarried out without any further adjuvants or in the case of unreactivecoupling partners in the presence of Lewis acids such as e.g. BF₃*OEt₂or Me₃SiCl (see M. Schlosser, Organometallics in Synthesis, John Wiley &Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994). Preferreddefinitions of the groups R^(8a), R^(8b), R^(8c) and R^(8d) are benzyl,substituted benzyl, trialkylsilyl, particularly preferablytrimethylsilyl, triisopropylsilyl, 4-methoxybenzyl and benzyl. If twoadjacent groups of the group consisting of R^(8a), R^(8b), R^(8c) andR^(8d) are linked together, these two groups are preferably part of abenzylideneacetal, 4-methoxybenzylideneacetal, isopropylketal orconstitute a 2,3-dimethoxy-butylene group which is linked via the 2 and3 positions of the butane with the adjacent oxygen atoms of the pyranosering. The group R′ preferably denotes hydrogen or C₁₋₄-alkyl,particularly preferably hydrogen, methyl or ethyl. The group R′ isinserted after the addition of the organometallic compound V or aderivative thereof to the gluconolactone VI. For this purpose thereaction solution is treated with an alcohol such as e.g. methanol orethanol or water in the presence of an acid such as e.g.methanesulphonic acid, toluenesulphonic acid, sulphuric acid orhydrochloric acid.

The synthesis of haloaromatic compound of formula IV may be carried outusing standard transformations in organic chemistry or at least methodsknown from the specialist literature in organic synthesis (see interalia J. March, Advanced Organic Reactions, Reactions, Mechanisms, andStructure, 4th Edition, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1992 and literature cited therein). Thesynthesis strategies described in the following provide a demonstrationof this, by way of example.

Synthesis strategy 1 (Diagram 2) shows the preparation of thehaloaromatic compound of formula II starting from a benzoylchloride anda second aromatic group which is converted by Friedel-Crafts acylationinto the diphenylketone derivative. This classic reaction has a widesubstrate breadth and is carried out in the presence of a catalyst whichis used in catalytic or stoichiometric amounts, such as e.g. AlCl₃,FeCl₃, iodine, iron, ZnCl₂, sulphuric acid or trifluoromethanesulphonicacid. Instead of the carboxylic acid chloride it is also possible to usethe carboxylic acid, an anhydride or ester thereof or the correspondingbenzonitrile. The reactions are preferably carried out in chlorinatedhydrocarbons such as e.g. dichloromethane and 1,2-dichloroethane attemperatures from −30 to 120° C., preferably at 30 to 100° C. However,solvent-free reactions or reactions in a microwave oven are alsopossible. In a second reaction step the diphenylketone is reduced to thediphenylmethane. This reaction may be carried out in two steps via thecorresponding diphenylmethanol or in one step. In the two-step variantthe ketone is reduced with a reducing agent such as for example a metalhydride such as e.g. NaBH₄, LiAlH₄ or iBu₂AlH to form the alcohol. Theresulting alcohol can be converted in the presence of a Lewis acid suchas for example BF₃*OEt₂, trifluoroacetic acid, InCl₃ or AlCl₃ with areducing agent such as e.g. Et₃SiH, NaBH₄, or Ph₂SiClH to form thedesired diphenylmethane. The one-step process starting from the ketoneto obtain the diphenylmethane may be carried out e.g. with a silane suchas e.g. Et₃SiH, a borohydride such as e.g. NaBH₄ or an aluminium hydridesuch as LiAlH₄ in the presence of a Lewis acid such as for exampleBF₃*OEt₂, tris(pentafluorophenyl)-borane, trifluoroacetic acid,aluminium chloride or InCl₃. The reactions are preferably carried out insolvents such as e.g. halogenated hydrocarbons such as dichloromethane,toluene or acetonitrile at temperatures of −30 to 150° C., preferably at20 to 100° C. Reductions with hydrogen in the presence of a transitionmetal catalyst such as e.g. Pd on charcoal are another possible methodof synthesis. Reductions according to Wolff-Kishner or variants thereofare also possible. The ketone is first of all converted with hydrazineor a derivative thereof, such as e.g.1,2-bis(tert-butyldimethylsilyl)hydrazine, into the hydrazone whichbreaks down under strongly basic reaction conditions and heating to formthe diphenylmethane and nitrogen. The reaction may be carried out in onereaction step or after isolation of the hydrazone or a derivativethereof in two separate reaction steps. Suitable bases include e.g. KOH,NaOH or KOtBu in solvents such as e.g. ethyleneglycol, toluene, DMSO,2-(2-butoxyethoxy)ethanol or t-butanol; solvent-free reactions are alsopossible. The reactions may be carried out at temperatures between 20 to250° C., preferably between 80 to 200° C. An alternative to the basicconditions of the Wolff-Kishner reduction is the Clemmensen reductionwhich takes place under acid conditions, which may also be used here.

The second synthesis strategy (Diagram 3) shows another possible way ofsynthesising the halogen-aromatic groups of formula II′ illustrated bythe example of a trimethylsilylacetylene-substituted diphenylmethane.Starting from an aromatic group which carries two groups selected fromamong iodine, bromine, chlorine or sulphonate such as e.g.trifluoromethylsulphonate, an alkyne group is attached via a transitionmetal-catalysed monocoupling to the more reactive end of thedihaloaromatic compound, the iodine-carbon bond (step 1). The catalystsused are for example elemental palladium or nickel or salts or complexesthereof. The reactions may be carried out with the alkyne itself ormetal acetylidene therefrom. If the alkyne itself is used, coupling maybe carried out in the presence of a base such as e.g. NEt₃ and aco-catalyst such as e.g. a copper salt such as CuI (Sonogashiracoupling). The reactions are not limited to trimethylsilylacetylene, butallow the use of a number of terminal alkynes. The reaction isextensively documented with all its variations in the literature (see P.J. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions,Wiley-VCH, Weinheim, 1997 and Angew. Chem. Int. Ed. 2003, 42, 1566-1568and literature cited therein). The other two steps for preparing thediphenylmethane derivatives comprise transfunctionalising thealkyne-substituted aromatic group to obtain a metallised (Mg, Li)aromatic group which may be prepared, for example, by a halogen-metalexchange as described hereinbefore (step 2). This metallised aromaticcompound which may be used directly or after further transmetallation,is added to a benzaldehyde derivative. This forms the diphenylmethanolshown in the diagram. Alternatively it is also possible to use a benzoicacid derivative such as e.g. a benzoic acid ester, anhydride, chlorideor the acid itself or the benzonitrile. Instead of the alcohol thecorresponding ketone is formed, which may also be obtained byFriedel-Crafts acylation as described above. Further reaction of boththe alcohol and the ketone to form the diphenylmethane derivative hasalready been described above (step 3). The trimethylsilylethynylatedaromatic halogen compound may however also be converted directly aftertransmetallation into the desired product (step 4). For this, thelithium or magnesium aromatic group obtained after a halogen-metalexchange is reacted with a benzylelectrophil such as e.g. a benzylbromide or chloride. The reaction may be carried out without or, betterstill, in the presence of a transition metal catalyst, such as e.g. acopper salt or a palladium complex (see e.g. Org. Lett. 2001, 3,2871-2874 and literature cited therein). The aromatic lithium ormagnesium group may however also be transmetallised first, for example,to obtain the corresponding boric acids, boric acid esters, stannanes,silanes or zinc compounds. Then it is attached by means of a transitionmetal such as e.g. palladium, nickel, rhodium, copper or iron to thebenzyl group (see L. Brandsma, S. F. Vasilevsky, H. D. Verkruijsse,Application of Transition Metal Catalysts in Organic Synthesis,Springer-Verlag, Berlin/Heidelberg, 1998). The reactions of thealkyne-substituted aromatic group to the intermediate product of formulaII′ according to steps 2 and 3 or step 4, which are illustrated by wayof example here for R³ denoting ethynyl or trimethylsilylethynyl, mayalso be carried out analogously with other R³-substituted aromaticgroups.

Synthesis strategy 3 (Diagram 4) shows an alternative form of synthesisstrategy 2, which is also illustrated using the example of an aromatictrimethylsilylethynyl group II′, but should not be limited thereto. Thesynthesis starts with an aromatic group which carries both a Hal group,which denotes a halogen atom chlorine, bromine or iodine, or apseudohalogen group, such as e.g. trifluoromethanesulphonate, and also ametallic centre M, such as e.g. a B(OH)₂, Si(OAlk)₃ or SnBu₃ group. Thetwo centres thus “activated” may be exchanged chemoselectively one afterthe other. Synthesis strategy 3 illustrates this with an example inwhich first of all the halogen atom Hal is exchanged for an alkynesubstituent in a transition metal-catalysed reaction such as e.g. theso-called Sonogashira coupling. In the second step the metallic centre Mis exchanged for a benzyl group which is activated e.g. as the benzylhalide in another transition metal-catalysed coupling, to obtain thedesired product (see e.g. Tetrahedron Lett. 2003, 44, 9255-9258 andliterature cited therein). Both steps may be carried out usingtransition metals such as e.g. palladium, rhodium, nickel, copper oriron, or complexes thereof. Both types of reaction are described indetail in the literature. The method is not restricted to that shownhere but may also involve reversing the sequence of the two reactionsteps. In this case, the metallic centre M is first linked to the benzylgroup and then the halogen or pseudohalogen group Hal is exchanged forthe alkyne.

In order to prepare compounds of general formula I, in process a)according to the invention, a compound of general formula II

wherein R′, R¹ to R⁵ are as hereinbefore defined andR^(8a), R^(8b), R^(8c), R^(8d) are as hereinbefore defined andindependently of one another represent for example acetyl, pivaloyl,benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, benzylor substituted benzyl or in each case two adjacent groups R^(8a),R^(8b), R^(8c), R^(8d) form a benzylideneacetal or isopropylideneketalor a 2,3-dimethoxy-butylene group which is linked via position 2 and 3of the butylene group to the oxygen atoms of the pyranose ring and formswith them a substituted dioxane,which may be obtained as hereinbefore described, is reacted with areducing agent in the presence of a Lewis or Brønsted acid.

Suitable reducing agents for the reaction include for example silanes,such as triethyl, tripropyl, triisopropyl or diphenylsilane, sodiumborohydride, sodium cyanoborohydride, zinc borohydride, boranes, lithiumaluminium hydride, diisobutylaluminium hydride or samarium iodide. Thereductions are carried out without or in the presence of a suitableBrønsted acid, such as e.g. hydrochloric acid, toluenesulphonic acid,trifluoroacetic acid or acetic acid, or Lewis acid, such as e.g. borontrifluoride etherate, trimethylsilyltriflate, titanium tetrachloride,tin tetrachloride, scandium triflate or zinc iodide. Depending on thereducing agent and the acid the reaction may be carried out in asolvent, such as for example methylene chloride, chloroform,acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane,ethanol, water or mixtures thereof at temperatures between −60° C. and120° C. One particularly suitable combination of reagents consists forexample of triethylsilane and boron trifluoride etherate, which isconveniently used in acetonitrile or dichloromethane at temperatures of−60° C. and 60° C. Moreover, hydrogen may be used in the presence of atransition metal catalyst, such as e.g. palladium on charcoal or Raneynickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol,ethanol, water or acetic acid, for the transformation described.

Alternatively, in order to prepare compounds of general formula Iaccording to process b) according to the invention, in a compound ofgeneral formula III

wherein R¹ to R⁵ are as hereinbefore defined andR^(8a) to R^(8d) denote one of the protective groups definedhereinbefore, such as e.g. an acyl, arylmethyl, acetal, ketal or silylgroup, and which may be obtained for example by reduction from thecompound of formula II as hereinbefore described, the protective groupsare cleaved.

Any acyl protecting group used is cleaved for example hydrolytically inan aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C. A trifluoroacetyl group ispreferably cleaved by treating with an acid such as hydrochloric acid,optionally in the presence of a solvent such as acetic acid attemperatures between 50 and 120° C. or by treating with sodium hydroxidesolution optionally in the presence of a solvent such as tetrahydrofuranor methanol at temperatures between 0 and 50° C.

Any acetal or ketal protecting group used is cleaved for examplehydrolytically in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

A trimethylsilyl group is cleaved for example in water, an aqueoussolvent mixture or a lower alcohol such as methanol or ethanol in thepresence of a base such as lithium hydroxide, sodium hydroxide,potassium carbonate or sodium methoxide. In aqueous or alcoholicsolvents, acids such as e.g. hydrochloric acid, trifluoroacetic acid oracetic acid are also suitable. For cleaving in organic solvents, such asfor example diethyl ether, tetrahydrofuran or dichloromethane, it isalso suitable to use fluoride reagents, such as e.g. tetrabutylammoniumfluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxane, methanol or diethylether.

In the reactions described hereinbefore, any reactive groups presentsuch as ethynyl, hydroxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for an ethynyl group may be thetrimethylsilyl or triisopropyl group. The 2-hydroxisoprop-2-yl group mayalso be used as a protective group.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be, forexample, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaricacid, succinic acid, lactic acid, citric acid, tartaric acid or maleicacid.

Moreover, the compounds obtained may be converted into mixtures, forexample 1:1 or 1:2 mixtures with amino acids, particularly withalpha-amino acids such as proline or phenylalanine, which may haveparticularly favourable properties such as a high crystallinity.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature, for example, particularly the methodsdescribed in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO2004/063209.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an inhibitory effecton the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

The biological properties of the new compounds may be investigated asfollows:

The ability of the substances to inhibit the SGLT-2 activity may bedemonstrated in a test set-up in which a CHO-K1 cell line (ATCC No. CCL61) or alternatively an HEK293 cell line (ATCC No. CRL-1573), which isstably transfected with an expression vector pZeoSV (Invitrogen, EMBLaccession number L36849), which contains the cDNA for the codingsequence of the human sodium glucose cotransporter 2 (Genbank Acc. No.NM_(—)003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport¹⁴C-labelled alpha-methyl-glucopyranoside (¹⁴C-AMG, Amersham) into theinterior of the cell in sodium-dependent manner.

The SGLT-2 assay is carried out as follows:

CHO-hSGLT2 cells are cultivated in Ham's F12 Medium (BioWhittaker) with10% foetal calf serum and 250 μg/ml zeocin (Invitrogen), andHEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calfserum and 250 μg/ml zeocin (Invitrogen). The cells are detached from theculture flasks by washing twice with PBS and subsequently treating withtrypsin/EDTA. After the addition of cell culture medium the cells arecentrifuged, resuspended in culture medium and counted in a Casy cellcounter. Then 40,000 cells per well are seeded into a white, 96-wellplate coated with poly-D-lysine and incubated overnight at 37° C., 5%CO₂. The cells are washed twice with 250 μl of assay buffer (HanksBalanced Salt Solution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mMMgSO₄ and 10 mM HEPES (pH7.4), 50 μg/ml of gentamycin). 250 μl of assaybuffer and 5 μl of test compound are then added to each well and theplate is incubated for a further 15 minutes in the incubator. 5 μl of10% DMSO are used as the negative control. The reaction is started byadding 5 μl of ¹⁴C-AMG (0.05 μCi) to each well. After 2 hours'incubation at 37° C., 5% CO₂, the cells are washed again with 250 μl ofPBS (20° C.) and then lysed by the addition of 25 μl of 0.1 N NaOH (5min. at 37° C.). 200 μl of MicroScint20 (Packard) are added to each welland incubation is continued for a further 20 min at 37° C. After thisincubation the radioactivity of the ¹⁴C-AMG absorbed is measured in aTopcount (Packard) using a ¹⁴C scintillation program.

To determine the selectivity with respect to human SGLT1 an analogoustest is set up in which the cDNA for hSGLT1 (Genbank Acc. No. NM000343)instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.

The compounds of general formula I according to the invention may forexample have EC50 values below 1000 nM, particularly below 200 nM, mostpreferably below 50 nM.

In view of their ability to inhibit the SGLT activity, the compounds ofgeneral formula I according to the invention and the correspondingpharmaceutically acceptable salts thereof are theoretically suitable forthe treatment and/or preventative treatment of all those conditions ordiseases which may be affected by the inhibition of the SGLT activity,particularly the SGLT-2 activity. Therefore, compounds according to theinvention are particularly suitable for the prevention or treatment ofdiseases, particularly metabolic disorders, or conditions such as type 1and type 2 diabetes mellitus, complications of diabetes (such as e.g.retinopathy, nephropathy or neuropathies, diabetic foot, ulcers,macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, edema and hyperuricaemia. These substances arealso suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The substances are alsosuitable for improving or restoring the functionality of pancreaticcells, and also of increasing the number and size of pancreatic betacells. The compounds according to the invention may also be used asdiuretics or antihypertensives and are suitable for the prevention andtreatment of acute renal failure.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of diabetes, particularly type 1 and type 2diabetes mellitus, and/or diabetic complications.

The dosage required to achieve the corresponding activity for treatmentor prevention usually depends on the compound which is to beadministered, the patient, the nature and gravity of the illness orcondition and the method and frequency of administration and is for thepatient's doctor to decide. Expediently, the dosage may be from 1 to 100mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg,preferably 1 to 100 mg, by oral route, in each case administered 1 to 4times a day. For this purpose, the compounds of formula I preparedaccording to the invention may be formulated, optionally together withother active substances, together with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include for examplethose which potentiate the therapeutic effect of an SGLT antagonistaccording to the invention with respect to one of the indicationsmentioned and/or which allow the dosage of an SGLT antagonist accordingto the invention to be reduced. Therapeutic agents which are suitablefor such a combination include, for example, antidiabetic agents such asmetformin, sulphonylureas (e.g. glibenclamide, tolbutamide,glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g.rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) andantagonists, PPAR-gamma/alpha modulators (e.g. KRP 297),alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIVinhibitors (e.g. LAF237, MK-431), alpha2-antagonists, insulin andinsulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.The list also includes inhibitors of protein tyrosinephosphatase 1,substances that affect deregulated glucose production in the liver, suchas e.g. inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase, lipid loweringagents such as for example HMG-CoA-reductase inhibitors (e.g.simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate),nicotinic acid and the derivatives thereof, PPAR-alpha agonists,PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterolabsorption inhibitors such as, for example, ezetimibe, bile acid-bindingsubstances such as, for example, cholestyramine, inhibitors of ileacbile acid transport, HDL-raising compounds such as CETP inhibitors orABC1 regulators or active substances for treating obesity, such assibutramine or tetrahydrolipostatin, dexfenfluramine, axokine,antagonists of the cannabinoid) receptor, MCH-1 receptor antagonists,MC4 receptor agonists, NPY5 or NPY2 antagonists or B3-agonists such asSB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltof such a compound combined with at least one of the active substancesdescribed above as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by inhibiting thesodium-dependent glucose cotransporter SGLT. These are preferablymetabolic diseases, particularly one of the diseases or conditionslisted above, most particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

Thus, for example, a pharmaceutical composition according to theinvention comprises a combination of a compound of formula I accordingto the invention or a physiologically acceptable salt of such a compoundand at least one angiotensin II receptor antagonist optionally togetherwith one or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. The Examples thatfollow are intended to illustrate the present invention withoutrestricting it:

Preparation of the Starting Compounds Example I

(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone

38.3 ml oxalyl chloride and 0.8 ml of dimethylformamide are added to amixture of 100 g of 5-bromo-2-chloro-benzoic acid in 500 mldichloromethane. The reaction mixture is stirred for 14 h, then filteredand separated from all volatile constituents in the rotary evaporator.The residue is dissolved in 150 ml dichloromethane, the solution iscooled to −5° C., and 46.5 g of anisole are added. Then 51.5 g ofaluminium trichloride are added batchwise so that the temperature doesnot exceed 5° C. The solution is stirred for another 1 h at 1-5° C. andthen poured onto ice. The organic phase is separated off and the aqueousphase is extracted another three times with dichloromethane. Thecombined organic phases are washed with aqueous 1 M hydrochloric acid,twice with 1 M sodium hydroxide solution and with saturated sodiumchloride solution. Then the organic phase is dried, the solvent isremoved and the residue is recrystallised in ethanol.

Yield: 86.3 g (64% of theory)

Mass spectrum (ESI⁺): m/z=325/327/329 (Br+Cl) [M+H]⁺

The following compounds are obtained analogously to Example I:

(1) (5-bromo-2-iodo-phenyl)-(4-ethoxy-phenyl)-methanone

Mass spectrum (ESI⁺): m/z=431/433 (Br) [M+H]+

(2) (5-bromo-2-chloro-phenyl)-(4-iodo-phenyl)-methanone

Example II

4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene

A solution of 86.2 g(5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mltriethylsilane in 75 ml dichloromethane and 150 ml acetonitrile iscooled to 10° C. Then with stirring 50.8 ml of boron trifluorideetherate are added so that the temperature does not exceed 20° C. Thesolution is stirred for 14 h at ambient temperature, before another 9 mltriethylsilane and 4.4 ml boron trifluoride etherate are added. Thesolution is stirred for a further 3 h at 45-50° C. and then cooled toambient temperature. A solution of 28 g potassium hydroxide in 70 ml ofwater is added and the mixture is stirred for 2 h. Then the organicphase is separated off and the aqueous phase is extracted another threetimes with diisopropylether. The combined organic phases are washedtwice with 2 M potassium hydroxide solution and once with aqueous sodiumchloride solution and then dried over sodium sulphate. After the solventhas been eliminated the residue is stirred in ethanol, separated offagain and dried at 60° C.

Yield: 50.0 g (61% of theory)

Mass spectrum (ESI⁺): m/z=310/312/314 (Br+Cl) [M+H]⁺

The following compounds are obtained analogously to Example II:

(1) 4-bromo-1-iodo-2-(4-ethoxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=434/436 [M+NH₄]⁺

(2) 4-bromo-1-chloro-2-(4-iodo-benzyl)-benzene

Example III

4-(5-bromo-2-chloro-benzyl)-phenol

A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in150 ml dichloromethane is cooled in the ice bath. Then 50 ml of a 1 Msolution of boron tribromide in dichloromethane are added, and thesolution is stirred for 2 h at ambient temperature. The solution is thencooled in the ice bath again, and saturated potassium carbonate solutionis added dropwise. At ambient temperature the mixture is adjusted withaqueous 1 M hydrochloric acid to a pH of 1, the organic phase isseparated off and the aqueous phase is extracted another three timeswith ethyl acetate. The combined organic phases are dried over sodiumsulphate, and the solvent is removed completely.

Yield: 13.9 g (98% of theory)

Mass spectrum (ESI⁻): m/z=295/297/299 (Br+Cl) [M−H]⁻

Example IV

[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane

A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mldichloromethane is cooled in the ice bath. Then 7.54 gtert-butyldimethylsilylchlorid in 20 ml dichloromethane are addedfollowed by 9.8 ml triethylamine and 0.5 g dimethylaminopyridine. Thesolution is stirred for 16 h at ambient temperature and then dilutedwith 100 ml dichloromethane. The organic phase is washed twice withaqueous 1 M hydrochloric acid and once with aqueous sodium hydrogencarbonate solution and then dried over sodium sulphate. After thesolvent has been eliminated the residue is filtered through silica gel(cyclohexane/ethyl acetate 100:1).

Yield: 16.8 g (87% of theory)

Mass spectrum (EI): m/z=410/412/414 (Br+Cl) [M]⁺

Example V 1-bromo-4-triisopropylsilylethynyl-benzene

Under argon 11.6 ml triisopropylacetylen and 14.4 ml triethylaminefollowed by 0.2 g copper iodide and 0.73 gbis-(triphenylphosphine)-palladium dichloride are added to anoxygen-free solution of 15.0 g 1-bromo-4-iodo-benzene in 150 ml drytetrahydrofuran. The solution is stirred for 16 h at ambient temperatureand then filtered through Celite and evaporated down. The residue ischromatographed through silica gel (cyclohexane).

Yield: 17.4 g (100% of theory)

Mass spectrum (ESI⁺): m/z=336/338 (Br) [M]⁺

The following compounds are obtained analogously to Example V:

(1) 4-bromo-1-(triisopropylsilylethynyl)-2-(4-ethoxy-benzyl)-benzene

4-bromo-1-iodo-2-(4-ethoxy-benzyl)-benzene is used as the startingmaterial for the coupling reaction described hereinbefore.

Mass spectrum (ESI⁺): m/z=471/473 (Br) [M+H]⁺

(2) [4-(5-bromo-2-chloro-benzyl)-phenylethynyl]-triisopropyl-silane

4-bromo-1-chloro-2-(4-iodo-benzyl)-benzene is used as starting material.

This compound may also be obtained according to Example X.

Example VI

(5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol

33.8 ml of a 1.6 M solution of n-butyllithium in hexane are addeddropwise under argon to a solution of 17.4 g1-bromo-4-triisopropylsilylethynyl-benzene in 120 ml dry tetrahydrofuranchilled to −78° C. The solution is stirred for 1 h at −70° C. Then 10.8g 5-bromo-2-fluoro-benzaldehyde dissolved in 30 ml of tetrahydrofuranare added dropwise over 15 min. The resulting solution is left in thecooling bath to warm up overnight to ambient temperature. Then water isadded and the mixture is extracted with ethyl acetate. The combinedorganic phase are dried over sodium sulphate, and the solvent isremoved. The residue is purified through silica gel (cyclohexane/ethylacetate 4:1).

Yield: 14.3 g (60% of theory)

Mass spectrum (ESI⁺): m/z=461/463 (Br) [M+H]⁺

The following compounds are obtained analogously to Example VI:

(1) (3-bromo-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol

Mass spectrum (ESI⁻): m/z=487/489 (Br) [M+HCOO]⁻

(2)(5-bromo-2-methoxy-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol

Mass spectrum (ESI⁺): m/z=473/475 (Br) [M+H]⁺

Example VII

[4-(5-bromo-2-fluoro-benzyl)-phenylethynyl]-triisopropyl-silane

A solution of 5.6 g(5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanoland 4.1 ml triethylsilane in 50 ml dichloromethane is cooled in the icebath. Then 4.7 ml trifluoroacetic acid are slowly added dropwise, andthe solution is stirred for 4 h at ambient temperature. The solution isdiluted with dichloromethane and washed with aqueous sodium hydrogencarbonate solution. After drying over sodium sulphate the solvent isremoved and the residue is purified using silica gel (cyclohexane).

Yield: 2.6 g (48% of theory)

Mass spectrum (EI): m/z=445/447 (Br) [M]+

The following compounds are obtained analogously to Example VII:

(1) [4-(3-bromo-benzyl)-phenylethynyl]-triisopropyl-silane

Mass spectrum (ESI⁺): m/z=427/429 (Br) [M+H]⁺

(2) [4-(5-bromo-2-methoxy-benzyl)-phenylethynyl]-triisopropyl-silane

In a departure from the process described hereinbefore the reactionsolution is stirred in the ice bath instead of at ambient temperatureuntil the reaction is complete.

Mass spectrum (ESI⁺): m/z=457/459 (Br) [M+H]⁺

Example VIII

4-bromo-2-brommethyl-1-chloro-benzene

4.0 g N-bromosuccinimide are slowly added to a solution of 5.0 g of4-bromo-1-chloro-2-hydroxymethyl-benzene and 5.9 g triphenylphosphine in50 ml of tetrahydrofuran chilled to 5° C. After 1 h stirring at ambienttemperature the precipitate is filtered off and the solvent iseliminated in vacuo. The residue is purified through silica gel(cyclohexane/ethyl acetate 50:1).

Yield: 4.9 g (76% of theory)

Mass spectrum (EI): m/z=282/284/286 (Br+Cl) [M]⁺

Example IX

(4-iodo-phenylethynyl)-triisopropyl-silane

Under argon 18.0 g sodium iodide (dry), 0.6 g copper iodide and 0.8 gN,N′-dimethyl-cyclohexane-1,2-diamine are added to a solution of 20.0 g(4-bromo-phenylethynyl)-triisopropyl-silane. The solution is refluxedwith stirring for 24 h and then cooled to ambient temperature. 1%ammonia solution (100 ml) is added and the mixture is extracted withethyl acetate. After drying over sodium sulphate the solvent is removedand the residue is purified using silica gel (cyclohexane).

Yield: 21.0 g (92% of theory)

Mass spectrum (EI): m/z=384 [M]+

Example X

[4-(5-bromo-2-chloro-benzyl)-phenylethynyl]-triisopropyl-silane

Under argon 0.66 ml of a 2 M solution of isopropylmagnesium chloride intetrahydrofuran are added dropwise to a solution of 0.50 g(4-iodo-phenylethynyl)-triisopropyl-silane in 2.2 ml dry tetrahydrofuranchilled to −25° C. The solution is stirred for 30 min at −25° C. andthen combined with 0.26 ml of a 1 M solution of CuCN*2 LiCl intetrahydrofuran (prepared by dissolving CuCN and LiCl in the ratio 1:2).Shortly afterwards, 0.35 g 4-bromo-2-bromomethyl-1-chlorbenzene areadded and the reaction mixture is brought up to −5° C. in the coolingbath. After 6 h stirring at −5° C. the solution is heated to ambienttemperature and stirred overnight. Then a mixture of saturated ammoniumchloride solution and 25% ammonia solution (9:1) is added and theresulting mixture is added to water. The organic phase is separated offand the aqueous phase is extracted with ethyl acetate, the combinedorganic phases are dried over sodium sulphate, and the solvent isremoved. The residue is purified through silica gel (cyclohexane).

Yield: 0.28 g (50% of theory)

Mass spectrum (EI): m/z=461/463/465 (Br+Cl) [M+H]⁺

Example XI

2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone

A solution of 20 g D-glucono-1,5-lactone and 98.5 ml N-methylmorpholinein 200 ml of tetrahydrofuran is cooled to −5° C. Then 85 mltrimethylsilylchloride are added dropwise so that the temperature doesnot exceed 5° C. The solution is then stirred for 1 h at ambienttemperature, 5 h at 35° C. and again for 14 h at ambient temperature.After the addition of 300 ml of toluene the solution is cooled in theice bath, and 500 ml of water are added so that the temperature does notexceed 10° C. The organic phase is then separated off and washed in eachcase once with aqueous sodium dihydrogen phosphate solution, water andsaturated aqueous sodium chloride solution. The solvent is removed, theresidue is taken up in 250 ml of toluene and the solvent is againremoved completely.

Yield: 52.5 g (approx. 90% pure)

Mass spectrum (ESI⁺): m/z=467 [M+H]⁺

Example XII

1-fluoro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

A solution of 4.46 g[4-(5-bromo-2-fluoro-benzyl)-phenylethynyl]-triisopropyl-silane in 30 mldry diethyl ether is cooled to −80° C. under argon. 11.8 ml of a 1.7 Msolution of tert-butyllithium in pentane are slowly added dropwise tothe cooled solution, and then the solution is stirred for 45 min at −80°C. Then a solution of 5.19 g of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 50 ml diethylether, chilled to −80° C., is added dropwise to this solution through atransfer needle. The resulting solution is stirred for 3 h at −78° C.Then a solution of 1.7 ml methanesulphonic acid in 50 ml of methanol isadded, the cooling bath is removed and the solution is stirred for 16 hat ambient temperature. The solution is then neutralised withethyldiisopropylamine and evaporated down to dryness. The residue ispurified through silica gel (dichloromethane/methanol 50:1->4:1).

Yield: 2.8 g (50% of theory)

Mass spectrum (ESI⁺): m/z=576 [M+NH₄]⁺

The following compounds are obtained analogously to Example XII:

(1)1-methoxy-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

Advantageously the reaction mixture is mixed with only a small excess ofmethanesulphonic acid.

Mass spectrum (ESI⁺): m/z=588 [M+NH₄]⁺

(2)1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=592/594 (Cl) [M+NH₄]⁺

Example XIII

1-fluoro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

A solution of 0.8 g1-fluoro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzeneand 0.5 ml triethylsilane in 6 ml dichloromethane and 10 ml acetonitrileis cooled to −10° C. 0.27 ml boron trifluoride etherate are addeddropwise to the cooled solution. The solution is then stirred for 3 h inthe ice bath. Aqueous sodium hydrogen carbonate solution is added to thesolution and then the mixture is extracted with ethyl acetate. Theorganic phase is dried over sodium sulphate, the solvent is removed andthe residue is taken up in 6 ml dichloromethane. Then 1.2 ml ofpyridine, 1.3 ml of acetic anhydride and 8 mg of 4-dimethylaminopyridineare added. The solution is stirred for 1 h at ambient temperature andthen combined with water. The mixture is extracted with dichloromethane,the organic phase is washed with 1 M hydrochloric acid and dried oversodium sulphate. After the solvent has been eliminated the residue ischromatographed through silica gel (cyclohexane/ethyl acetate 4:1->1:1).

Yield: 0.23 g (23% of theory)

Mass spectrum (ESI⁺): m/z=714 [M+NH₄]⁺

The following compounds are obtained analogously to Example XIII:

(1)1-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=726 [M+NH₄]⁺

(2)1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethynyl-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=730/732 (Cl) [M+NH₄]⁺

Example XIV

1-(2,3,4,6-Tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4-triisopropylsilylethynyl-benzyl)-benzene

A solution of 2.6 g[4-(3-bromo-benzyl)-phenylethynyl]-triisopropyl-silane in 20 ml drydiethyl ether is cooled to −80° C. under argon. 7.9 ml of a 1.7 Msolution of tert-butyllithium in pentane are slowly added dropwise tothe cooled solution, and then the solution is stirred for 30 min at −80°C. A solution of 3.2 g2,3,4,6-tetrakis-β-(trimethylsilyl)-D-glucopyranone in 30 ml diethylether chilled to −80° C. is then added dropwise to this solution througha transfer needle. The resulting solution is stirred for 2 h at −78° C.and then another solution of 1.0 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 10 ml diethylether chilled to −80° C. is added dropwise. After another hour'sstirring at −78° C. a solution of 2 ml methanesulphonic acid in 20 ml ofmethanol is added, the cooling bath is removed and the solution isstirred for 16 h at ambient temperature. The solution is thenneutralised with ethyldiisopropylamine, the solvent is removedcompletely and the residue is taken up in 50 ml of toluene. 8.5 mlethyldiisopropylamine are added, and the solution is cooled in the icebath. Then 4.3 ml acetic anhydride and 0.15 g 4-dimethylaminopyridineare added. The solution is stirred for 2 h at ambient temperature andthen combined with aqueous sodium hydrogen carbonate solution. It isextracted with ethyl acetate, the organic phases are dried over sodiumsulphate, and the solvent is removed. The residue is chromatographedthrough silica gel (cyclohexane/ethyl acetate 4:1->1:3).

Yield: 2.0 g (46% of theory)

Mass spectrum (ESI⁺): m/z=726 [M+NH₄]⁺

The following compound is obtained analogously to Example XIV:

(1)1-(triisopropylsilylethynyl)-4-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=770 [M+NH₄]⁺

Example XV

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-(4-triisopropylsilylethynyl-benzyl)-benzene

1.2 ml triethylsilane and 0.36 ml boron trifluoride etherate are addeddropwise to an ice-cooled solution of 1.0 g1-(2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4-triisopropylsilylethynyl-benzyl)-benzeneand 25 μl water in 10 ml acetonitrile. The solution is then stirred for3 h in the ice bath and for 1 h at ambient temperature. Then thesolution is again cooled in the ice bath, and another 1.2 mltriethylsilane and 0.36 ml boron trifluoride etherate are added. Thesolution is stirred for a further 0.5 h in the ice bath and 2 h atambient temperature. Aqueous sodium hydrogen carbonate solution is thenadded to the solution, and the resulting solution is extracted withethyl acetate. The organic phase is dried over sodium sulphate and thesolvent is removed.

Yield: 0.78 g (81% of theory)

Mass spectrum (ESI⁺): m/z=696 [M+NH₄]⁺

The following compound is obtained analogously to Example XV:

(1)1-(triisopropylsilylethynyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzene

Example XVI

1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene

A solution of 4.0 g[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42ml dry diethyl ether is cooled to −80° C. under argon. 11.6 ml of a 1.7M solution of tert-butyllithium in pentane are slowly added dropwise tothe cooled solution, and then the solution is stirred for 30 min at −80°C. This solution is then added dropwise through a transfer needle, whichis cooled with dry ice, to a solution of 4.78 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethylether chilled to −80° C. The resulting solution is stirred for 3 h at−78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml ofmethanol is added and the solution is stirred for 16 h at ambienttemperature. The solution is then neutralised with solid sodium hydrogencarbonate, ethyl acetate is added and the methanol is removed togetherwith the ether. Aqueous sodium hydrogen carbonate solution is added tothe remaining solution and extracted four times with ethyl acetate. Theorganic phases are dried over sodium sulphate and evaporated down. Theresidue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane andthe solution is cooled to −10° C. After the addition of 4.4 mltriethylsilane 2.6 ml boron trifluoride etherate are added dropwise sothat the temperature does not exceed −5° C. After the addition has endedthe solution is stirred for another 5 h at −5 to −10° C. and thenquenched by the addition of aqueous sodium hydrogen carbonate solution.The organic phase is separated off and the aqueous phase is extractedfour times with ethyl acetate. The combined organic phase are dried oversodium sulphate, the solvent is removed and the residue is purifiedusing silica gel. The product then obtained is an approx. 6:1 mixture ofβ/α which can be converted into the pure β-anomer by total acetylationof the hydroxy groups with acetic anhydride and pyridine indichloromethane and recrystallising the product in ethanol. The productthus obtained is converted into the title compound by reacting inmethanol with 4 M potassium hydroxide solution.

Yield: 1.6 g (46% of theory)

Mass spectrum (ESI⁺): m/z=398/400 (Cl) [M+H]⁺

Example XVII

1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene

10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 mltriethylamine and 0.39 g N,N-bis-(trifluoromethanesulphonyl)-aniline in10 ml dry dichloromethane. The solution is stirred for 4 h at ambienttemperature and then combined with aqueous sodium chloride solution. Itis extracted with ethyl acetate, the organic extracts are dried oversodium sulphate, and the solvent is removed. The residue ischromatographed through silica gel (dichloromethane/methanol 1:0->4:1).

Yield: 0.33 g (64% of theory)

Mass spectrum (ESI⁺): m/z=530/532 (Cl) [M+NH₄]⁺

Example XVIII

2,3,4,6-Tetra-O-benzyl-D-glucopyranone

4 g freshly activated molecular sieve 4 Å and 3.3 gN-methylmorpholine-N-oxide are added to a solution of 10.0 g2,3,4,6-tetra-O-benzyl-α-D-glucopyranose in 140 ml dichloromethane. Thesolution is stirred for 20 min at ambient temperature, before adding 0.3g of tetrapropylammonium perruthenate. After 2 h stirring at ambienttemperature the solution is diluted with dichloromethane and filteredthrough Celite. The filtrate is washed with aqueous sodium thiosulphatesolution and water and then dried over sodium sulphate. After thesolvent has been eliminated the residue is chromatographed throughsilica gel (cyclohexane/ethyl acetate 4:1).

Yield: 8.2 g (82% of theory)

Mass spectrum (ESI⁺): m/z=539 [M+H]⁺

Example XIX

1-(2,3,4,6-Tetra-O-benzyl-1-hydroxy-D-glucopyranos-1-yl)-3-[4-(tert-butyl-dimethyl-silyloxy)-benzyl]-4-methyl-benzene

A solution of 0.34 g[4-(5-bromo-2-methyl-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 3 mldry tetrahydrofuran is cooled to −80° C. under argon. 0.54 ml of a 1.6 Msolution of n-butyllithium in hexane are added dropwise to the cooledsolution, and the solution is stirred for 1.5 h at −78° C. A solution of0.43 g 2,3,4,6-tetra-O-benzyl-D-glucopyranone in 2.5 ml oftetrahydrofuran chilled to −80° C. is added dropwise to this solution bymeans of transfer needle. The resulting solution is stirred for 5 h at−78° C. The reaction is quenched with a solution of 0.1 ml acetic acidin 1 ml of tetrahydrofuran and heated to ambient temperature. Thenaqueous sodium hydrogen carbonate solution is added and the mixture isextracted four times with ethyl acetate. The organic phases are driedover sodium sulphate and evaporated down. The residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 15:1->4:1).

Yield: 0.48 g (approx. 88% pure)

Mass spectrum (ESI⁺): m/z=868 [M+H]⁺

Example XX

1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzene

A solution of 0.48 g (approx. 88% pure)1-(2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl)-3-[4-(tert-butyl-dimethyl-silyloxy)-benzyl]-4-methyl-benzenein 3.5 ml dry acetonitrile is cooled to −40° C. under argon. 0.13 mltriisopropylsilane and 0.08 ml boron trifluoride etherate are addeddropwise to the cooled solution. The solution is stirred for 3 h at −35°C., before another 0.02 ml of triisopropylsilane and 0.01 ml of borontrifluoride etherate are added. After a further 2 h at −40° C. aqueouspotassium carbonate is added and the solution is stirred for 1 h atambient temperature. Then it is diluted with water and extracted fourtimes with ethyl acetate. The organic phase is dried over sodiumsulphate, concentrated and chromatographed through silica gel(cyclohexane/ethyl acetate 10:1->4:1).

Yield: 0.24 g (68% of theory). Mass spectrum (ESI⁺): m/z=738 [M+NH₄]⁺

Example XXI

1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(tetrahydrofuran-3-yloxy)-benzyl]-4-methyl-benzene

0.10 g tetrahydrofuran-3-yl toluene-4-sulphonate are added to a mixtureof 0.24 g1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzeneand 0.13 g caesium carbonate in 2.5 ml of dimethylformamide. The mixtureis stirred for 4 h at 65° C., before water is added. It is extractedthree times with ethyl acetate, the organic phase is dried over sodiumsulphate and the solvent is removed. The residue is purified throughsilica gel purified (cyclohexane/ethyl acetate 10:1->4:1).

Yield: 0.23 g (78% of theory). Mass spectrum (ESI⁺): m/z=808 [M+H]⁺

Example XXII

1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulphonyloxy)-benzyl]-4-methyl-benzene

A solution of 0.62 g1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-(4-hydroxybenzyl)-4-methyl-benzenein 4.5 ml dry dichloromethane is cooled to −10° C. under argon. 0.14 mlof pyridine and a solution of 0.3 g trifluoromethanesulphonic anhydridein 0.5 ml dichloromethane are added to the cooled solution. The solutionis stirred for 0.5 h at −5 to −10° C., before aqueous sodium hydrogencarbonate solution is added. The mixture is extracted three times withdichloromethane, the combined organic phases are washed with aqueous 1 Mhydrochloric acid and dried over sodium sulphate. After the solvent hasbeen eliminated the residue is chromatographed through silica gel(cyclohexane/ethyl acetate 15:1->7:1).

Yield: 0.62 g (84% of theory)

Mass spectrum (ESI⁺): m/z=853 [M+H]⁺

Example XXIII

1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trimethylsilylethynyl)-benzyl]-4-methyl-benzene

Under argon, 27 mg copper iodide, 49 mgbis-(triphenylphosphine)-palladium dichloride, 0.30 ml triethylamine andfinally 0.14 ml of trimethylsilylacetylene are added to a solution of0.60 g1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulphonyloxy)-benzyl]-4-methyl-benzenein 3 ml of dimethylformamide. The flask is tightly sealed and stirredfor 4 h at 90° C. Then another 20 mg ofbis-(triphenylphosphine)-palladium dichloride and 0.6 mltrimethylsilylacetylene are added, and the solution is stirred for afurther 4 h at 90° C. Then aqueous sodium hydrogen carbonate solution isadded, the mixture is extracted three times with ethyl acetate, and thecombined organic phases are dried over sodium sulphate. After thesolvent has been eliminated the residue is chromatographed throughsilica gel (cyclohexane/ethyl acetate 40:1->10:1).

Yield: 0.45 g (80% of theory)

Mass spectrum (ESI⁺): m/z=818 [M+NH₄]⁺

Preparation of the End Compounds Example 1

1-chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzene

0.16 ml iodocyclopentane are added to a mixture of 0.25 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 gcaesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirredfor 4 h at 45° C., before another 0.1 g caesium carbonate and 0.05 mliodocyclopentane are added. After another 14 h stirring at 45° C.aqueous sodium chloride solution is added and the mixture is extractedwith ethyl acetate. The organic phase is dried over sodium sulphate, thesolvent is removed and the residue is purified using silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 0.23 g (78% of theory)

Mass spectrum (ESI⁺): m/z=466/468 (Cl) [M+NH₄]⁺

The following compounds are obtained analogously to Example 1:

(2)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene

The reaction is carried out with tetrahydrofuran-3-yl(S)-toluene-4-sulphonate as the coupling partner.

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

(3)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene

The reaction is carried out with tetrahydrofuran-3-yl(R)-toluene-4-sulphonate as the coupling partner.

Mass spectrum (ESI⁺): m/z=451/453 (Cl) [M+H]⁺

(4)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydrofuran-2-on-3-yloxy)-benzyl]-benzene

The reaction is carried out with 3-bromobutyrolactone as the couplingpartner.

Mass spectrum (ESI⁺): m/z=465/467 (Cl) [M+H]⁺

(5)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclobutyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=452/454 (Cl) [M+NH₄]⁺

(6)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=480/482 (Cl) [M+NH₄]⁺

(7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydropyran-4-yloxy)-benzyl]-benzene

Mass spectrum (ESI⁺): m/z=487/489 (Cl) [M+Na]⁺

(8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-acetyl-piperidin-4-yloxy)-benzyl]-benzene

The reaction is carried out with1-acetyl-4-methylsulphonyloxy-piperidine as the electrophile.

Mass spectrum (ESI⁺): m/z=506/508 (Cl) [M+H]⁺

(9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-tert-butyloxycarbonylpiperidin-4-yloxy)-benzyl]-benzene

The reaction is carried out with1-tert-butyloxycarbonyl-4-methylsulphonyloxy-piperidine as theelectrophile.

Mass spectrum (ESI⁺): m/z=586/588 (Cl) [M+Na]⁺

Example 10

1-(β-D-glucopyranos-1-yl)-4-methyl-3-[4-(tetrahydrofuran-3-yloxy)-benzyl]-benzene

A mixture of 0.21 g1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(tetrahydrofuran-3-ylox)-benzyl]-4-methyl-benzeneand 0.1 g of 10% palladium hydroxide on charcoal in 3 ml of ethylacetate is shaken for 24 h at ambient temperature under a hydrogenpressure of 1 atm. Then the same amount of catalyst is added again andthe mixture is shaken for a further 24 h under a hydrogen atmosphere.Then the catalyst is filtered off, the filtrate is evaporated down andthe residue is chromatographed through silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 0.06 g (49% of theory)

Mass spectrum (ESI⁺): m/z=448 [M+NH₄]⁺

Example 11

1-(β-D-glucopyranos-1-yl)-4-methyl-3-[4-(2-trimethylsilyl-ethyl)-benzyl]-benzene

A mixture of 0.29 g1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-4-methyl-3-[4-(trimethylsilylethynyl)-benzyl]-benzeneand 0.25 g of 10% palladium hydroxide on charcoal in 3 ml of ethylacetate is shaken for 24 h at ambient temperature under a hydrogenpressure of 1 atm. Then another 0.2 g of catalyst are added and thesolution is shaken for a further 20 h under a hydrogen atmosphere. Thenthe catalyst is filtered off, the filtrate is evaporated down and theresidue is chromatographed through silica gel (dichloromethane/methanol1:0->5:1).

Yield: 0.08 g (51% of theory)

Mass spectrum (ESI⁺): m/z=462 [M+NH₄]⁺

Example 12

1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene

25 mg of copper iodide, 44 mg of bis-(triphenylphosphine)-palladiumdichloride, 0.30 ml triethylamine and finally 0.14 ml oftrimethylsilylacetylene are added under argon to a solution of 0.32 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzenein 3 ml of dimethylformamide. The flask is tightly sealed and stirredfor 8 h at 90° C. Then another 25 mg ofbis-(triphenylphosphine)-palladium dichloride and 0.1 mltrimethylsilylacetylene are added, and the solution is stirred for afurther 10 h at 90° C. Then aqueous sodium hydrogen carbonate solutionis added, the mixture is extracted three times with ethyl acetate, andthe combined organic phases are dried over sodium sulphate. After thesolvent has been eliminated the residue is dissolved in 5 ml of methanoland combined with 0.12 g potassium carbonate. The mixture is stirred for1 h at ambient temperature and then neutralised with 1 M hydrochloricacid. Then the methanol is evaporated off, the residue is combined withaqueous sodium chloride solution and extracted with ethyl acetate. Theorganic extracts collected are dried over sodium sulphate, and thesolvent is removed. The residue is chromatographed through silica gel(dichloromethane/methanol 1:0->5:1).

Yield: 0.095 g (40% of theory)

Mass spectrum (ESI⁺): m/z=406/408 (Cl) [M+NH₄]⁺

This compound may also be obtained according to Example 14.

Example 131-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(piperidin-4-yloxy)-benzyl]-benzene

2 ml trifluoroacetic acid are added to a solution of 0.19 g1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-tert-butlyoxycarbonylpiperidin-4-yloxy)-benzyl]-benzenein 4 ml dichloromethane. The solution is stirred for 1.5 h at ambienttemperature and then diluted with ethyl acetate and made basic withaqueous potassium carbonate solution. The organic phase is separated offand the aqueous phase is extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and the solvent iseliminated entirely.

Yield: 0.060 g (38% of theory)

Mass spectrum (ESI⁺): m/z=464/466 (Cl) [M+H]⁺

Example 14

1-fluoro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene

0.33 ml of a 1 M solution of tetrabutylammoniumfluorid intetrahydrofuran are added to a solution of 0.23 g1-fluoro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(triisopropylsilylethynyl-benzyl)-benzenein 1.5 ml of tetrahydrofuran. The solution is stirred for 1 h at ambienttemperature. Then 1 ml of methanol and 1.5 ml of 4 M potassium hydroxidesolution are added and the solution is stirred for a further hour atambient temperature. The solution is neutralised with 1 M hydrochloricacid and then the methanol is evaporated off. The residue is combinedwith aqueous sodium chloride solution and extracted with ethyl acetate.The organic extracts collected are dried over sodium sulphate, and thesolvent is removed. The residue is chromatographed through silica gel(dichloromethane/methanol 19:1->2:1).

Yield: 0.060 g (49% of theory)

Mass spectrum (ESI⁺): m/z=390 [M+NH₄]⁺

The following compounds are obtained analogously to Example 14:

(15) 1-(β-D-glucopyranos-1-yl)-3-(4-ethynyl-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=372 [M+NH₄]⁺

(16) 1-ethynyl-4-(β-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=416 [M+NH₄]⁺

(17) 1-methoxy-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene

Mass spectrum (ESI⁺): m/z=402 [M+NH₄]⁺

The compound according to Example (12)(1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene) mayalso be synthesised analogously to Example 14. Optionally, theintermediate stage,1-chloro-4-(2,3,4,6-tetra-O-acteyl-β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,which is obtained after desilylation with tetrabutylammonium fluoride,may be purified by recrystallisation from ethanol.

Mass spectrum (ESI⁺): m/z=406/408 (Cl) [M+NH₄]⁺

The following compounds are also prepared analogously to theabove-mentioned Examples and other methods known from the literature:

Ex. Structure (18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

Some examples of formulations will now be described in which the term“active substance” denotes one or more compounds according to theinvention, including the salts thereof. In the case of one of thecombinations with one or additional active substances as describedpreviously, the term “active substance” also includes the additionalactive substances.

Example A Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains: active substance 100.0 mg lactose  80.0 mg cornstarch  34.0 mg polyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

Example B Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains: active substance 150.0 mg powdered lactose  89.0 mgcorn starch  40.0 mg colloidal silica  10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate  1.0 mg 300.0 mg

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

Weight of tablet: 300 mg die:  10 mm, flat

Example C Hard Gelatine Capsules Containing 150 mg of Active SubstanceComposition:

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx.  87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example D Suppositories Containing 150 mg of Active SubstanceComposition:

1 suppository contains: active substance   150.0 mg polyethyleneglycol1500   550.0 mg polyethyleneglycol 6000   460.0 mg polyoxyethylenesorbitan monostearate   840.0 mg 2,000.0 mg

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example E Ampoules Containing 10 mg Active Substance Composition:

active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilledwater ad  2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

Example F Ampoules Containing 50 mg of Active Substance Composition:

active substance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilledwater ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

1.-22. (canceled)
 23. Process for preparing compounds of general formula II

wherein R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R^(8a), R^(8b), R^(8c), R^(8d) independently of one another have one of the meanings given for the groups R⁶, R^(7a), R^(7b), R^(7c), denote a benzyl group or a R^(a)R^(b)R^(c)Si group or a ketal or acetal group, while in each case two adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclic ketal or acetal group or a 1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, and alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or C₁₋₃-alkoxy and benzyl groups may also be substituted by a di-(C₁₋₃-alkyl)amino group; and R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl, aryl or aryl-C₁₋₃-alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen; while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, preferably phenyl groups; and R¹ to R⁵ and R⁶, R^(7a), R^(7b), R^(7c) have the meanings given in claims 1, wherein an organometallic compound (V) which may be obtained by halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R⁵ are as hereinbefore defined, and optionally subsequent transmetallation, is added to a gluconolactone of general formula VI

wherein R^(8a), R^(8b), R^(8c), R^(8d) are as hereinbefore defined, and then reacting the adduct obtained with water or an alcohol R′—OH, where R′ denotes optionally substituted C₁₋₄-alkyl, in the presence of an acid and optionally the product obtained in the reaction with water wherein R′ denotes H is converted in a subsequent reaction with an acylating agent into the product of formula II wherein R′ denotes (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C₁₋₃-alkyl)-carbonyl, which may be substituted as specified.
 24. Process according to claim 23, wherein the organometallic compound (V) is a lithium or magnesium compound.
 25. (canceled)
 26. Compound of general formula IV

wherein Hal denotes chlorine, bromine or iodine and the groups R¹, R², R³, R⁴ and R⁵ are defined as in claim
 1. 27. Compound of formula IV according to claim 26, characterised by the formula

wherein Hal denotes chlorine, bromine or iodine and the groups R¹, R², R⁴ and R⁵ are defined according to claim 1 and the group R³ is selected from the group B according to claim
 26. 28. Compound of general formula II

wherein R′ denotes H, C₁₋₄-alkyl, (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(C₁₋₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R^(8a), R^(8b), R^(8c), R^(8d) independently of one another have one of the meanings given for the groups R⁶, R^(7a), R^(7b), R^(7c), or denote a benzyl group or a R^(a)R^(b)R^(c)Si group or a ketal or acetal group, while in each case two adjacent groups R^(8a), R^(8b), R^(8c), R^(8d) may form a cyclic ketal or acetal group or a 1,2-di(C₁₋₃-alkoxy)-1,2-di(C₁₋₃-alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, and alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or C₁₋₃-alkoxy and benzyl groups may also be substituted by a di-(C₁₋₃-alkyl)amino group; and R^(a), R^(b), R^(c) independently of one another denote C₁₋₄-alkyl, aryl or aryl-C₁₋₃-alkyl, while the alkyl or aryl groups may be mono- or polysubstituted by halogen; while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, preferably phenyl groups; and R¹ to R⁵ are defined as in one or more of claim
 1. 